PART IV Systemic Immunomodulatory Drugs
13
Systemic Corticosteroids
STEPHEN E. WOLVERTON AND ELIZABETH A. RANCOUR
QUESTIONS
Q13.1 Concerning prednisone and cortisone, what is (1) the active
form of each drug, (2) the enzyme necessary for this conversion,
and (3) the effect of severe liver disease on this conversion?
(Pgs. 134, 135)
Q13.2 What are ‘physiologic dose’ levels for (1) prednisone,
(2) prednisolone, (3) dexamethasone, (4) methylprednisolone,
and (5) triamcinolone? (Table 13.1, Pg. 151)
Q13.3 What are several cells that systemic corticosteroid (CS) can
induce to undergo apoptosis, and the disease states that may
logically be successfully treated because of this apoptosis?
(Table 13.2, Pgs. 136, 139x2)
Q13.4 Compared with other uses of systemic CS, how do the dose
timing, dosing strategy, and drug choice differ when treating
patients with androgen excess disorders of adrenal origin?
(Pg. 141)
Q13.5 What are several pros and cons of intramuscular (IM) CS
injections versus oral dosing? What are several dermatoses for
which IM Kenalog has the best risk:benefit ratio and overall logic
of use? (Table 13.5, Box 13.4, Pg. 141)
Q13.6 What are the two key issues that determine the rapidity
of systemic CS dose tapering? Which of these two key issues
matters primarily when dosing is below ‘physiologic’ dose
levels? (Box 13.8, Box 13.9, Table 13.14, Pgs. 142, 149, 151x2)
A B B R E V I AT I O N S U S E D I N T H I S C H A P T E R
ACTH Adrenocorticotropic hormone (corticotropin)
AE Adverse effects/events
AP-1 Activating protein-1
BPAg2 Bullous pemphigoid antigen-2
CBG Cortisol-binding globulin
CHF Congestive heart failure
CI Confidence interval (95% CI)
CRF Corticotropin-releasing factor
CS Corticosteroid
DEXA Dual energy X-ray absorptiometry
DHEA-S Dehydroepiandrosterone-sulfate
GCR Glucocorticoid receptor
HPA Hypothalamic-pituitary-adrenal (axis)
IFN Interferon
IκB Inhibitor kappa B
Q13.7 What are several of the most important adverse effects
of systemic CS that can lead to significant, irreversible
morbidity (as well as measures to prevent/monitor for these
complications)? How do patient comorbidities impact the risk of
these conditions? (Table 13.7, Pgs. 142, 144)
Q13.8 What are at least four to five of the potentially life-
threatening complications of systemic CS, and what are some
of the important measures to prevent and/or monitor for these
complications? (Table 13.8, Pg. 143)
Q13.9 Concerning response to physical stressors, which part of
the hypothalamic-pituitary-adrenal (HPA) axis is (1) quickest
to be suppressed, (2) quickest to recover, and (3) overall most
important to stress responsiveness? (Pg. 148)
Q13.10 What are some of the ‘back-up’ mechanisms the body has
to minimize the likelihood of CS-induced HPA-axis suppression?
(Pgs. 149x2)
Q13.11 What are some general principles (1) to maximize CS safety
(Box 13.8), (2) to taper CS therapy (Box 13.9), and (3) to convert
CS to alternate-day dosing (Table 13.14)? What two criteria
should be met before making this conversion? (Pgs. 151, 154x2)
Q13.12 What are two to three adverse effects of systemic CS not
decreased by comparable doses of systemic CS using alternate-
day therapy? (Pg. 154)
IL Interleukin
IM Intramuscular
IV Intravenous
MC Mineralocorticoid
NFκB Nuclear factor kappa B
NSAID Nonsteroidal anti-inflammatory drug
PPD Purified protein derivative
PUD Peptic ulcer disease
RR Relative risk
SEGRA Selective glucocorticoid receptor agonist(s)
SJS Stevens–Johnson syndrome
SLE Systemic lupus erythematosus
SWS (Cortico-)Steroid withdrawal syndrome
TEN Toxic epidermal necrolysis
TNF Tumor necrosis factor
133
134 PA RT I V Systemic Immunomodulatory Drugs

Systemic Corticosteroids
Kendall described compound E (cortisone) in 1935.1 A Mayo
Clinic group first described the use of cortisone and adrenocorti-
cotropic hormone (ACTH) in patients with rheumatoid arthritis
in 1948.1 In 1950, Hench and colleagues presented the first report
concerning the basic effects and toxicities of corticosteroids (CS).2
Sulzberger and associates’ 1951 report described the use of cor-
tisone and ACTH in a variety of inflammatory dermatoses.3 This
report on CS radically changed the therapeutic approach of der-
matologists. As the list of CS-responsive dermatoses grew, so did
the list of potential adverse effects (AE). In 1961, Reichling and
Kligman suggested alternate-day CS use.4 This was an important
step toward reducing AE and yet maintaining significant anti-
inflammatory effects over the 48-hour period between doses.
Two major advances in CS therapy occurred during the 1970s
and 1980s. Adjunctive therapy with immunosuppressive drugs,
such as azathioprine and cyclophosphamide, has been used
increasingly to attain a ‘CS-sparing’ effect. These adjunctive drugs
allow lower CS doses to be used, which lessens the risk of seri-
ous AE while maintaining an adequate immunosuppressive effect.
High-dose pulse intravenous (IV) methylprednisolone therapy
was increasingly used through the 1980s. Quicker remission with
lower risk from therapy is the goal of this method of CS adminis-
tration. In the 1990s to today, further recognition of efficacy and
safety of low-dose CS has led to the primary use today as a ‘bridge’
to alternative CS-sparing treatments.
One population study estimated that 0.5% of patients (preva-
lence) in industrialized countries with a total population of 1.2
billion are on at least 3 months of continuous CS. Another study
estimated that 32 million prescriptions for systemic CS are written
annually in the United States. In addition to the cost of AE of CS,
the striking frequency of CS use in these countries sets the stage
for chance overlap of two relatively frequent events (CS use plus
a common AE).
This chapter covers the pharmacology and clinical use of sys-
temic CS. Particular attention is given to the risks of systemic
CS, especially focusing on measures to minimize the risk of these
important complications. The physician who is thoroughly famil-
iar with these measures will use systemic CS more comfortably
and wisely, to the benefit of many grateful patients.
This chapter includes special sections covering the following
areas: (1) normal hypothalamic-pituitary-adrenal (HPA)-axis
function; (2) intramuscular (IM) CS administration; (3) pulse IV
CS administration; (4) HPA-axis suppression; and (5) therapeutic
guidelines for safe and effective CS use.
Pharmacology (Table 13.1)
Structure
The basic structure of all CS consists of three hexane rings and
one pentane ring.1,5 The combined ring structure is known as the
cyclopentanoperhydrophenanthrene nucleus. The rings are desig-
nated by letters A, B, C, and D, and each carbon is assigned a
number from 1 to 21 (Fig. 13.1). The designations alpha (α, away
from the CS receptor) and beta (β, toward the CS receptor) refer
to the position of any added molecules in reference to the stereo-
chemical plane.
Q13.1 Cortisone and cortisol (hydrocortisone) both possess
a 4,5 double bond and a ketone (carbonyl) group at the 3 posi-
tion.5,6 Cortisone, which is an inactive form, has a ketone at the
11 position. The active form, cortisol (hydrocortisone), is formed
through hepatic conversion of the 11-ketone to an 11-hydroxyl
group catalyzed by 11β hydroxysteroid dehydrogenase. Of note,
topical CS must have an 11-hydroxyl group to be effective. The
addition of a 1,2 double bond results in increased glucocorti-
coid activity and decreased rate of metabolic degradation. This
results in prednisone (with an 11-ketone group), and through
11-hydroxylation, the active analog prednisolone is formed; with

TABLE
13.1 Pharmacology Key Concepts—Systemic Corticosteroids5–10

Equivalent Dose (mg) Glucocorticoid Plasma Half-Life Biologic Half-Life

Corticosteroid Physiologic Dose Potencya MC Potency (Min) (H)
Short-Acting
Cortisone 25 0.8 2+ 30–90 8–12
Cortisol (hydrocorti- 20 1 2+ 60–120 8–12
sone)

Intermediate-Acting
Prednisone 5 4 1+ 60 24–36
Prednisolone 5 4 1+ 115–212 24–36
Methylprednisolone 4 5 0 180 24–36
Triamcinolone 4 5 0 78–188 24–36

Long-Acting
Dexamethasone 0.75 2–-30 0 100–300 36–72

Betamethasone 0.6–0.75 20–30 0 100–300 36–72

aGlucocorticoid
potency is expressed in a relative scale without specific units of measure; this relative potency number is inversely related to the equivalent dose in the first column.
MC, Mineralocorticoid.
 CHAPTER 13 Systemic Corticosteroids 135

11β hydroxysteroid dehydrogenase catalyzing this conversion as The primary endogenous carrier protein is cortisol-binding
well. Methylprednisolone is formed through the addition of a globulin (CBG, transcortin).5 Overall, 80% to 90% of endogenous
6-methyl group to prednisolone, which leads to slightly increased cortisol is bound to CBG; the free fraction represents the active
glucocorticoid potency. form. CBG is a low-capacity, high-affinity binding system. Albu-
The addition of fluorine to hydrocortisone at the 9-α position min (CS-binding albumin) represents a low-affinity, high-capacity
leads to increased glucocorticoid, but significant mineralocorticoid binding reserve. The avidity with which synthetic CS bind to these
(MC) activity.5,6 The resulting compound is 9-α fluorohydrocor- carrier proteins is less than the avidity with which endogenous
tisone (fludrocortisone). This compound is the basic structure of cortisol is bound. Thus, for synthetic CS a greater free fraction is
most fluorinated topical CS. In general, the MC effect is decreased available. Prednisolone is reported to bind to carrier proteins with
in topical CS by the masking of the 16- or the 17-hydroxyl group greater affinity than other synthetic forms, with resultant potential
with various ester links to side chains (e.g., acetonide, valerate, for displacement of endogenous cortisol from the protein-binding
propionate, dipropionate). sites. There are several systemic conditions which alter the levels of
With systemic CS, 9-α fluorohydrocortisone with an added CBG (Box 13.1). Generally, low protein states increase the risk of
1,2 double bond is also modified further.5,6 By adding a 16-α AE secondary to an increased level of free CS. Additionally, high-
hydroxyl group (triamcinolone), a 16-α methyl group (dexa- dose therapy and prolonged CS treatment results in a greater pro-
methasone), or a 16-β methyl group (betamethasone), three com- portion of free CS in the body.
pounds with high glucocorticoid and low MC effects are formed. Overall, CS are widely distributed to most body tissues. All
Because all three drugs have an 11-hydroxyl group, these three endogenous and synthetic CS are well distributed into fetal tissue,
compounds are in biologically active forms (without requir- with the exception of prednisone.5
ing 11β-hydroxysteroid dehydrogenase). All CS have a hydroxyl
group at the 17 position (17-hydroxycorticosteroids). Androgenic Metabolism and Excretion
steroid compounds have a 17-ketone group and a 19-carbon basic
ring structure (17-ketosteroids). Q13.1 Of importance is that the action of 11β hydroxysteroid
dehydrogenase in the liver is necessary to convert cortisone to
cortisol (hydrocortisone), and to convert prednisone to predniso-
Absorption and Distribution lone.5 The type I isoform of 11β hydroxysteroid dehydrogenase
Exogenous CS are absorbed in the upper jejunum.1 More than catalyzes conversion of endogenous cortisone (inactive) to cortisol
50% of prednisone is absorbed. Food delays, but does not reduce, (active), and converts exogenous prednisone (inactive) to pred-
the amount of prednisone absorbed. Peak plasma levels are reached nisolone (active). The type II isoform of the above enzyme reverses
30 to 100 minutes after the drug is taken. this conversion, reverting back to the inactive forms. Type II iso-
form is found in mineralocorticoid tissues.7 The relative presence
of these isoforms can determine the likelihood of (1) inflamma-
OH
tory and autoimmune dermatoses, and (2) response to exogenous
prednisone administration. It is important to note that dexameth-
O
asone and betamethasone are active independently of this enzyme.
18 Of these four CS, only cortisol and prednisolone are biologically
OH OH
12 active. Severe liver disease may impair this conversion, although
11 13 17
D 16
the traditional teaching to use the active form of these drugs (such
C
19 14 as prednisolone) with significant liver disease may be just part of
15
1 9 this ‘story’ (plus the liver has tremendous ‘reserve’). Regardless,
2 10 8 the administration of prednisolone (rather than prednisone) to
A B patients with advanced liver disease would be appropriate. In addi-
3 5 7
4 6 tion, liver disease may result in decreased serum albumin, which
O
would increase the free fraction of CS as discussed above.
The plasma half-lives of the various synthetic CS do not correlate
Hydrocortisone (Cortisol) well with the duration of biologic activity1 (see Table 13.1). A much

• BOX 13.1 Cortisol-Binding Globulin

HO O Conditions with Decreased Cortisol-Binding Globulin (CBG)

H3C OH *result in increased amount of endogenous and synthetic corticosteroid (CS)
O free fraction
Hypothyroidism
Liver disease
H3C H
Renal disease
Obesity
H H
Conditions with Increased CBG
*result in decreased amount of endogenous and synthetic CS free fraction
O
Estrogen therapy
Pregnancy
Prednisone Hyperthyroidism
• Fig. 13.1 Corticosteroid structure—prednisone, cortisol.
136 PA RT I V Systemic Immunomodulatory Drugs

more important measure of duration of activity is the duration of

ACTH suppression after the administration of a single dose of a given
CS. They are generally divided into short, intermediate, and long-act-
ing. This duration of activity correlates well with glucocorticoid and
anti-inflammatory effects.8,9 There is an inverse correlation between
the duration of action and the relative MC effect of the various CS.
Mechanism of Action
Q13.3 The most important immunosuppressive and anti-inflam-
matory effects of systemic CS are listed in Table 13.2. In addi-
tion, the mechanisms responsible for the most important CS
AE are listed in later in the chapter in Table 13.7. The interested

TABLE
13.2 Immunosuppressive and Anti-inflammatory Effects of Corticosteroids5,10,18,19

Corticosteroid Action Mechanism and Biologic Result

Effects On Glucocorticoid Receptor (GCR)
Normal response Upon ligand (CS) binding, the GCR is activated and translocates to the nucleus, binding to glucocorticoid-
response elements of multiple genes. CS can function as an agonist or antagonist for these genes—
GCR is ubiquitous throughout body.

Transcription Factor Effects

NFκB inhibition Increased IκB production, direct NFκB binding; net result ↓ production of multiple cytokines such as IL-1,
TNF-α, adhesion molecules, growth factors, etc.
AP-1 inhibition Decreased production of multiple cytokines; similar cytokine spectrum to NFκB.

Apoptosis Induction
Lymphocyte apoptosis Apoptosis of autoreactive T cells (in autoimmune disorders) and neoplastic T cells (in various lympho-
mas); AP-1 and caspase cascade probably involved in process.
Eosinophil apoptosis Apoptosis of eosinophils with potential implications for various allergic disorders.

Signal Transduction
Phospholipase A2 inhibition CS effect probably mediated indirectly via ↑ lipocortin-1 (now called ‘annexin’).
↓ ‘Downstream’ eicosanoids As a result of phospholipase A2 inhibition, ↓ production of various prostaglandins, leukotrienes, 12-HETE
and 15-HETE inflammatory mediators.
Cyclo-oxygenase 2 (COX-2) inhibition ↓ Eicosanoid production generated by this inducible (with inflammation) enzyme; CS effect on COX-2 >>
COX-1.

Effects on Various WBC Subsets and Other Immunologic Cells

B cells With higher CS doses significant B-cell effect, reduced immunoglobulin production.
T cells Greater CS effect on T cells (CD4 > CD8 effect) at lower doses compared with above B-cell effect; net
result ↑ Tregs and ↓ IL-2 production and resultant amplification effect.
Other lymphocyte subsets ↓ Natural killer (NK) cell activity, ↓ antibody-dependent cellular cytotoxicity mediated by K cells.
PMN ↓ PMN marginization, ↓ chemotaxis, small effect on microbicidal respiratory burst; also ↓ apoptosis of
PMN (in contrast with T cells and eosinophils above).
Mast cells Inhibit degranulation, with resultant ↓ release histamine, kinins, other mediators.
Monocytes, macrophages ↓ Monocyte maturation; ↓ access to inflammatory sites, ↓ IL-1 and IFN-γ release.
Langerhans cells ↓ Characteristic surface markers, impaired antigen processing and presentation.
Eosinophils, basophils Reduced numbers and function both cell types, ↓ recruitment to inflammatory sites.
Fibroblasts ↓ Production of collagen, ground substance, fibronectin and collagenase.
Membrane stabilization Both lysosomal and cell membrane stabilization; probable role in mast cell, PMN, other inflammatory cell
effects.
Bottom line generalizations CS overall effects—cell trafficking > cellular function; cellular immunity > humoral immunity; major
portion of effects mediated via above cytokine alterations.

Vascular Effects
Angiogenesis ↓ Angiogenesis in wound healing and with proliferative lesions (hemangiomas).
Vasoconstriction Net result of vasocortin and vasoregulin, potentiate response to catecholamines.

Decreased permeability Decreased vascular smooth muscle response to histamine and bradykinin.

AP-1; Activating protein-1; CS, corticosteroid; HETE, hydroxyeicosatetraenoic acid; IFN, interferon; IκB, inhibitor kappa B; IL, interleukin; NFκB, nuclear factor kappa B; PMN, polymorphonuclear cell; TNF,
tumor necrosis factor; WBC, white blood cell.

reader should take sufficient time to thoroughly understand these
two tables in order to have a broad understanding of the overall
benefits and risks of systemic CS. There will next be a concise
discussion on normal HPA-axis function, glucocorticoid effects,
and MC effects. This section concludes with relatively new infor-
mation on glucocorticoid receptors (GCR), CS resistance and
tachyphylaxis, transcription factors, and apoptosis. The reader is
encouraged to pursue reviews concerning newer scientific data on
the CS mechanisms of action.10,11
Normal Hypothalamic-Pituitary-Adrenal-Axis Function. It is
important to understand the normal function of the HPA axis
in order to better understand the potential for HPA-axis suppres-
sion by synthetic CS. For further background information, several
reviews are particularly helpful.12–17
The primary stimulus for release of endogenous cortisol
originates in the hypothalamus. The tropic hormone is known
as corticotropin-releasing factor (CRF). ACTH is subsequently
released by the anterior pituitary. ACTH is produced from the
prohormone pro-ACTH/endorphin. There are approximately
10 bursts of ACTH release throughout the day. The greatest
frequency of these bursts occurs in the early morning hours
during a normal sleep cycle. The zona fasciculata of the adre-
nal cortex is then stimulated to produce and release cortisol.
ACTH also stimulates adrenal androgen synthesis. However,
ACTH is not significantly involved in the release of the MC
aldosterone.
There are three main controls of endogenous cortisol produc-
tion. These are discussed in the summary ‘HPA axis in a nutshell’
(Box 13.2).
Glucocorticoid Effects (Table 13.3). CS plays an important
teleologic role in maintaining adequate blood glucose levels for
brain function.5 Gluconeogenesis generates glucose at the expense
of amino acids derived from endogenous proteins. CS also pro-
duces peripheral insulin resistance, which impedes glucose absorp-
tion by various body tissues. In addition, glycogen storage in the
liver is enhanced. Lipid stores are stimulated to undergo lipoly-
sis, generating increased amounts of triglycerides from which to
derive energy.
The net effect is a catabolic state that produces carbohydrates at
the expense of protein and fat stores.5 Through gluconeogenesis,
proteins from muscle, trabecular bone (especially vertebral and
hip), dermal connective tissue, and vascular proteins are metabo-
lized. Lipolysis results in triglyceride release, with additional fat
redistribution (lipodystrophy) to body sites that are characteristic
of the habitus for Cushing syndrome.
Mineralocorticoid Effects. Aldosterone is the primary endog-
enous MC hormone. The primary aldosterone effect is sodium
reabsorption and resultant water reabsorption at the proximal
tubule site in the kidneys. Sodium is exchanged for potassium,
which leads to hypokalemia when there is excessive MC effect.
ACTH has no direct control on MC production. The primary
MC control mechanisms are through the renin–angiotensin sys-
tem and serum potassium levels.12,14 CS with significant MC
effects (such as hydrocortisone) have a similar effect on sodium,
potassium, and fluid balance as aldosterone (Table 13.3). Long-
acting CS (such as dexamethasone and betamethasone) have
essentially no MC effect (see Table 13.1).
Glucocorticoid Receptor Physiology and Corticosteroid Resis-
tance. There is only one GCR, but a diverse collection of isoforms,
which accounts for endogenous glucocorticoid effects as well as the
pharmacological effects of synthetic CS (resulting in both benefi-
cial and AE).18,19 This cytosolic receptor is expressed throughout
CHAPTER 13 Systemic Corticosteroids 137
tissues, but there is considerable heterogeneity in sensitivity and
biological responses. The GCR functions directly as a transcrip-
tion factor, which upon translocation to the nucleus binds directly
to various glucocorticoid responsive elements of multiple genes in
DNA. In addition, the ligand–GCR complex can activate other
transcription factors, as detailed in the next section. CS exerts its
effects through both genomic and nongenomic actions.
Splice variants, translational isoforms, posttranslational modi-
fications, and polymorphisms give a molecular basis for sensitivity
of glucocorticoid responsiveness. There are rare cases of hereditary
glucocorticoid resistance, in which there are mutations in the GCR
gene.20 In clinical practice, relative resistance at the GCR in otherwise
healthy individuals is much more common than previously recog-
nized. In addition, relative resistance is because of altered CS bio-
availability, altered ligand binding to GCR, or altered translocation
of the activated GCR complex to the nucleus.21 Conceptually, this
resistance could represent a negative feedback system of sorts, with
downregulation of GCR after prolonged or high-dose CS therapy.
Corticosteroids and Transcription Factors. There are two well-
described transcription factors with a central role in amplification
of the inflammatory response (Fig. 13.2). These transcription
factors are nuclear factor kappa B (NFκB) and AP-1. NFκB is
biologically inactive as long as it is bound to inhibitor kappa B
(IκB).22,23 Free NFκB translocates to the nucleus, where it induces
transcription of numerous cytokines including (1) ‘immuno-
awakening’ cytokines (interleukin [IL]-1β, tumor necrosis factor
• BOX 13.2 Hypothalamic-Pituitary-Adrenal Axis in a
Nutshell10,12–14
Components of Hypothalamic-Pituitary-Adrenal (HPA) Axis and
Hormone Produced
Hypothalamus—corticotrophin-releasing factor (CRF)
Pituitary (anterior)—adrenocorticotropic hormone (ACTH)
Adrenal—cortisol (same as hydrocortisone)
Basal and Stress Levels of Corticosteroid (CS) Production
Basal production of cortisol—20–30 mg daily
Basal production in prednisone equivalents—5–7.5 mg daily
Maximal stress production of cortisol—300 mg daily
Maximal stress production in prednisone equivalents—75 mg daily
‘Minor stress’ production of cortisol—probably two to three times basal
production
Response of Various Components to Exogenous CS and
Subsequent ‘Stress’
Hypothalamus—first to be suppressed, first to recover full function; is most
critical component for adequate stress responsiveness
Adrenal—slower to be suppressed, much slower to recover full function
Regulatory Mechanisms and Sources of Variability
Circadian variations—CRF (and thus ACTH) have innate diurnal variations
tied to sleep cycle (highest production mid-sleep, lowest late afternoon)
Negative feedback—increased cortisol levels reduce CRF and ACTH production
Stress response—increased CRF release and subsequently ACTH release
Back-Up Mechanisms for CS Production in Setting of Adrenal
Insufficiency
CRF alternate sites of production—cerebral cortex and limbic system, which
can be released by acetylcholine and serotonin
Alternative inducers of ACTH release—catecholamines, vasopressin
All the above means serve to maintain glucose homeostasis
ACTH has no role in endogenous mineralocorticoid production.
138 PA RT I V Systemic Immunomodulatory Drugs

TABLE
13.3 Physiologic Glucocorticoid and Mineralocorticoid Effects5,10,18,19

Glucocorticoid Effectsa MC Effectsb

Glucose Metabolism Aldosterone Effects—Endogenous
Gluconeogenesis at expense of protein catabolism Major effect is sodium and water retention
Peripheral insulin resistance—reduced glucose entry into cells This effect is primarily at proximal tubule in kidney
Glycogen storage in liver Potassium is excreted in exchange sodium at this site
Lipid Metabolism Corticosteroid Effects—Exogenous
Lipolysis releasing triglycerides as source of ‘energy’ Endogenous/exogenous cortisol significant MC effects
Fat redistribution to central locations See Table 13.1 for MC effect of various CS
Regulation Of Above Processes Regulation of Endogenous Aldosterone
ACTH (pituitary) induces release of cortisol (adrenal) ACTH has no role in aldosterone production

Negative feedback loop to hypothalamus (site of CRF production) Regulation primarily by renin–angiotensin, potassium
aConceptually, allthe glucocorticoid effects are prioritized to maintain brain glucose homeostasis.
bMajorpriority for MC is to maintain sodium and fluid homeostasis, including a normal blood pressure.
ACTH, Adrenocorticotropic hormone; CRF, corticotropin-releasing factor; CS, corticosteroid; MC, mineralocorticoid.

“Activation signals”
B

IκB kinase

A E
(NFκΒ/ΙκΒ)

Corticosteroids
D
C NFκB-free (active)
Especially (Direct binding)
IL-Iβ and F
TNF-α
Various proinflammatory
cytokines, adhesion molecules

Release from cell

A “Normally” NFκB is bound by IκB (inhibitor κB) and rendered inactive as a transcription factor.
B Many “activation signals” (see text) which incite an inflammatory response lead to production
of IkB kinases, resulting in free (active) NFκB.
C The free form of NFκB serves as a transcription factor for a multitude of proinflammatory
cytokines and adhesion molecules (see text).
D Among the cytokines produced are IL-1α and TNF-α which form a (+) feedback loop further
stimulating release of free NFκB.
E Corticosteroids production of IκB, resulting in free NFκB.
F Corticosteroids also directly bind to free NFkB, inhibiting the transcription factor.
• Fig. 13.2 Nuclear factor kappa B (NFκB) transcription factor and corticosteroids. IL, Interleukin; IκB, inhib-
itor kappa B; TNF, tumor necrosis factor.

[TNF]-α), (2) ‘immunomodulatory’ cytokines (IL-2, IL-8), (3)
growth factors, (granulocyte-colony stimulating factor [G-CSF],
granulocyte-macrophage colony-stimulating factor [GM-CSF]),
(4) adhesion molecules (intercellular adhesion molecule 1 [ICAM-
1], E-selectin), (5) receptors (IL-2 receptor), and (6) proinflamma-
tory enzymes (cyclooxygenase-2 [COX-2], phospholipase A2).22
CS reduce the effects of NFκB in two ways.22,23 The CS-GCR
complex leads to increased IκB formation, leading to subsequent
NFκB binding by this inhibitory protein. The GCR/CS complex can
also directly bind to NFκB, thus inhibiting this transcription factor.
By either means, there can be a dramatic reduction of a wide variety of
components of the inflammatory response via this mechanism of CS.
AP-1 consists of either c-jun homodimers or c-jun/c-fos het-
erodimers, which bind to a common deoxyribonucleic acid (DNA)
site, the AP-1 binding site.10,24 There is tremendous overlap with
the inflammatory response genes induced by AP-1 and NFκB.25
 CHAPTER 13 Systemic Corticosteroids 139

In general, transrepression by GCR/CS complex of proinflamma- • BOX 13.3 Systemic Corticosteroid Indications
tory cytokines (such as IL-1β, TNF-α, interferon regulatory factor 3
[IRF-3]) accounts for most of anti-inflammatory effects of CS. IRF-3 Bullous Dermatoses
is a member of the interferon regulatory transcription factor family Pemphigus vulgaris/superficial formsa 29–37
and plays an important role in the innate immune system. In contrast, Bullous pemphigoida 38–43
transactivation by the GCR/CS complex of various regulatory pro- Mucous membrane/cicatricial pemphigoid123–125
teins is responsible for most CS AE (such as diabetes, glaucoma). As Herpes gestationis126,127
Epidermolysis bullosa acquisita128
such, selective glucocorticoid receptor agonist(s) (SEGRA) that favor
Linear IgA bullous dermatosis129,130
transrepression were developed as therapeutic agents with reduced Stevens–Johnson syndrome/TENa 44–53
AE. However, more recent data show that the transactivation poten- Erythema multiforme majora
tial of GR is indispensable for its anti-inflammatory properties.26
Corticosteroid-Induced Apoptosis. Apoptosis is an orderly pro- Autoimmune Connective Tissue Diseases
cess of programmed cell death. The process is a biologically active, Lupus erythematosus131–133 (systemica)
noninflammatory sequence of cellular changes that occur with an Dermatomyositisa 134–138
intact plasma membrane despite nuclear fragmentation. Q13.3 Systemic sclerosis or diffuse morphea
CS can directly induce apoptosis in lymphocytes and eosino- Eosinophilic fasciitis
phils.27 CS can induce apoptosis at least in part through down- Mixed connective tissue disease
Relapsing polychondritis
regulation of the CD3 molecule of T cells; this molecule plays an
important role in T-cell activation.28 There can also be an indirect Vasculitis
effect on lymphocytes and eosinophils through CS-induced sup- Cutaneous139–141
pression of cytokines essential to cellular survival.27 Systemic142–145
The logical application of these facts is an underlying explanation
for CS effects in autoimmune disorders (apoptosis of autoreactive T Neutrophilic Dermatoses
cells), allergic disorders (apoptosis of eosinophils), and certain neo- Pyoderma gangrenosum146–152
plastic disorders (apoptosis of malignant T cells). It is doubtful that Behçet disease/aphthous ulcers153–155
the ability of CS to induce apoptosis is limited to these cell types. Sweet syndrome156,157

Clinical Use
Food and Drug Administation-Approved
Indications and Off-Label Dermatologic Uses
Q13.3 Many of the common CS-responsive dermatoses are listed in
Box 13.3. A few disorders are discussed selectively to illustrate various
principles of CS therapy. Reference citations for many other dermato-
ses not discussed specifically in the text are listed in Box 13.3 as well.
Overall, well-controlled studies of CS use in the following der-
matoses are quite uncommon. In clinical practice, it is actually
quite easy in most cases to have a relatively high level of certainty
about the benefits of CS in an individual patient through tapering
the dose (the disease flares) and cautiously raising the dose (disease
control returns). Definitions of importance to both the Clinical
Use and Therapeutic Guidelines sections are listed in Table 13.4.
Pemphigus Vulgaris. The best-studied purely dermatologic indi-
cation for systemic CS therapy is pemphigus vulgaris. The emphasis
here is high-dose CS therapy, with use of adjunctive ‘steroid-sparing’
immunosuppressive therapy. CS are appropriate at the start of therapy
for any relatively severe case of pemphigus vulgaris that has no abso-
lute contraindications to CS use. Adjunctive therapy is generally used
with a choice of azathioprine, mycophenolate mofetil, methotrexate,
cyclosporine, cyclophosphamide, rituximab, intravenous immune
globulin (IVIg), or plasmapheresis.29–33 Anti-inflammatory antibi-
otics, such as the tetracyclines, as well as CS-sparing immunosup-
pressive medications have been used for milder cases of pemphigus
vulgaris and for pemphigus foliaceus. Pulse methylprednisolone as
well as rituximab are other options, which may be indicated to attain
rapid disease control in more severe cases of pemphigus vulgaris.
Current management includes prednisone doses no greater than
2 mg/kg daily in divided doses. In general, it is reasonable to start
prednisone at 1 to 1.5 mg/kg daily, increasing to the above dose
Dermatitis/Papulosquamous Dermatoses
Contact dermatitis54
Atopic dermatitis55
Exfoliative erythroderma56
Lichen planus158–162
Other Dermatoses
DRESS syndrome
Sarcoidosis163–165
Sunburn166 or photodermatitis
Urticaria (severea)167
Androgen excess (acne/hirsutism)57,58
Prevention of isotretinoin-induced acne fulminans
aUSFood and Drug Administration-approved indications.
DRESS, Drug reaction with eosinophilia and systemic symptoms.
range very selectively as indicated for more severe cases of pemphi-
gus vulgaris. Disease control is usually attained by 4 to 6 weeks.
Given this adequate disease control, the divided dose should be con-
solidated into a single daily dose and tapered rapidly to the 40-mg
daily range. Azathioprine or related immunosuppressive drugs can
be added at the time of prednisone tapering in many cases. For
more severe cases it is wise to add the ‘CS-sparing’ agent at the start
of therapy. Management of oral involvement needs to be reason-
ably aggressive, both to limit progression to more serious cutaneous
involvement and to maintain adequate fluid and nutrition intake.34
Juvenile pemphigus vulgaris is overall similar to that just described,
with CS doses adjusted for body weight.35,36 The challenge of man-
aging paraneoplastic pemphigus has been reviewed by Anhalt.37
Bullous Pemphigoid. In patients with bullous pemphigoid,
moderate doses of CS up to 1 mg/kg daily are used.38 The CS
course is typically given for a defined duration of time (generally
3–6 months or less), ideally achieving a physiologic dose range
within 1 to 2 months. Nonsteroidal immunosuppressive drugs
140 PA RT I V Systemic Immunomodulatory Drugs

TABLE
13.4 Some Definitions Used in This Chapter Pertaining To Corticosteroid Therapy

Dosing Level Definitions

Decrement Amount of reduction in CS dose—either a fixed percentage or fixed interval decrease
Increment Amount of increase in CS dose, guided by the urgency to attain disease control
Induction Initial CS dose focused on quickly attaining disease control
Maintenance Relatively constant dose of CS to maintain disease control attained by induction dose
Minimal effective The lowest dose of CS just adequate to almost completely control the disease process
Pharmacologic Generally considered to be any dose above physiologic levels (see text)
Physiologic Dose of exogenous CS which is similar to the quantity of endogenous CS produced
Replacement Is a synonym of physiologic dose—term also used to refer to endogenous MC levels
Supraphysiologic Is a synonym of pharmacologic dose
Tapering Any effort to reduce the CS dose, given that reasonable disease control is attained

Dosing Frequency or Duration Definitions

Alternate-day CS doses given every other day—result is an ‘on’ day and an ‘off’ day
Burst Short course of CS (generally 2–3 weeks or less) to control self-limited disease
Consolidation Change from a divided dose to a single daily dose without changing the daily dose; necessary step before tapering
Divided Any dosing frequency which is more frequent than daily dosing; usually BID or QID
‘Off’ day With alternate-day therapy, day in which CS is omitted (or lower dose is given)
‘On’ day With alternate-day therapy, day in which CS is administered (or higher dose is given)

Pulse Usually represents a very brief course (5–7 days) of very high dose (10–15 mg/kg per day) of intravenous methyl-
prednisolone (see text for other usage of this term)

CS, Corticosteroid; MC, mineralocorticoid.

(‘CS-sparing’ drugs) should be the mainstay of therapy if the dis-
ease persists beyond this time. As with most indications for systemic
CS, randomized controlled trials are few in number.39 One such
trial noted that topical CS was overall equivalent to systemic CS
for patients with bullous pemphigoid.40 It is indeed counterintuitive
that patients with widespread intact blisters could benefit from topi-
cal CS alone: experience dictates that systemic CS and appropriate
‘CS-sparing’ measures are still of central importance in this setting.41
In general, 60 to 80 mg daily (∼1 mg/kg daily) of prednisone in
divided doses is successful in eliminating new blister formation within
several weeks. Should the patient not respond to this dose, or require
a high maintenance dose, adjunctive immunosuppressive therapy
can be added. In the absence of new blisters over 5 to 7 days, the
prednisone dose can be gradually tapered. Contrary to prior reports,
Schmidt and coworkers reported that disease activity can be success-
fully monitored by following bullous pemphigoid antigen (BPAg2)
180 titers.42 Deaths still occasionally occur in older patients with
more extensive involvement; more conservative management using
alternatives to CS may help lessen the risk of sepsis in this age group.43
Stevens–Johnson Syndrome and Toxic Epidermal Necroly-
sis. There is still significant controversy regarding the use of sys-
temic CS for the spectrum of Stevens–Johnson syndrome (SJS)
and toxic epidermal necrolysis (TEN). Trends toward the use of
cyclosporine for these patients has taken some of the heat off the
debate. A recent meta-analysis and review of 96 studies found
CS and cyclosporine were the most promising systemic immu-
nomodulating therapies for SJS/TEN, although all analyses had
limitations.44 A significant number of studies support routine CS
therapy.45–47 A majority of studies, however, present data support-
ing routine use of burn unit care in the absence of systemic CS
therapy.48–52 These studies report a higher fatality rate, particularly
from sepsis, in CS-treated patients, than in patients managed in a
burn unit without CS therapy.
Proponents of routine systemic CS use suggest that for SJS and
TEN patients, systemic CS treatment early in the disease course
(before significant sloughing of skin), followed by rapid tapering
of CS, may be beneficial and even life saving.53 After widespread
sloughing occurs (>10% of total surface area), the risk of infection
clearly outweighs the potential CS benefits. Of importance is that
drug and infectious precipitators be sought and eliminated if pos-
sible. Should CS therapy be indicated, up to 2 to 2.5 mg/kg daily
of IV methylprednisolone in divided doses is generally used ini-
tially, with relatively rapid tapering to more moderate doses when
new blister formation ceases.
Acute Dermatitis. Severe acute contact dermatitis caused by
poison ivy/poison oak is a classic situation in which a 2- to 3-week
burst of systemic CS therapy is usually successful at minimal risk
to the patient.54 The potential for ‘rebound’ disease activity as a
result of prednisone courses of less than 10 to 14 days is important
to consider. Cases with widespread cutaneous involvement (or sig-
nificant facial involvement) treated early in their course typically
respond rapidly. Doses up to 1 mg/kg prednisone daily (gener-
ally 40–60 mg daily) tapered over 2 to 3 weeks yield adequate
improvement with minimal risk of rebound flare after cessation
of therapy. A simple approach that is easy for patients to follow
uses just 20 mg prednisone tablets. The patient receives 5 days
 CHAPTER 13 Systemic Corticosteroids 141

TABLE
13.5 Comparison of Oral Versus Intramuscular Corticosteroid Administration19,61,62

Issue Oral Administration Intramuscular Administration

Absorption
Compliance
Duration of therapy
Patient illness affecting dosing
Patient participation in dosing
Physician level of control
Reproduces diurnal variation
Reasonably predictable
Variable based on patient reliability
Any duration possible
Requires ‘cooperative’ GI tract
Requires active patient participation
Can vary the doses based on disease activity and
adverse effects
With a.m. dosing reproduces diurnal variation
somewhat
Highly variable from patient to patient
Guaranteed that dose is administered
Must use short-, intermediate-, and long-acting
IM versions
Can be given with nausea/vomiting
Patient in a passive role
Can be certain the patient received the medication
Constant levels without diurnal variance

Tapering Precise tapering possible Gradual tapering as drug metabolized

GI, Gastrointestinal; IM, intramuscular.

each of 60, 40, and 20 mg of prednisone. Various ‘dose packs’ of
prednisone and methylprednisolone typically do not provide an
adequate dose (to rapidly attain disease control) for an adequate
duration (to avoid a rebound flare).
Acute flares of chronic atopic, nummular, or contact derma-
titis can be managed in a similar fashion, although a recent sys-
tematic review did not find evidence strong enough to determine
optimal delivery or duration of systemic CS in atopic dermatitis
and discouraged their use because of short- and long-term AE and
an unfavorable risk–benefit profile.55 Because of rebound flaring,
use of CS should ideally be limited to short courses as a bridge
to CS-sparing agents. Maintenance CS therapy is best avoided in
these settings. Doses of prednisone significantly less than 1mg/kg
daily will commonly suffice for acute flares of chronic dermatitis
subsets.
Exfoliative Erythroderma. Exfoliative erythroderma man-
agement commonly requires systemic CS therapy.56 Given that
psoriasis has been excluded, exfoliative erythroderma refractory to
aggressive topical management or to phototherapy may respond
to prednisone up to 1 mg/kg daily. This dose is tapered rapidly to
low-dose alternate-day therapy. In erythroderma patients, a low-
dose daily or alternate-day therapy at or near physiologic levels for
an additional 2 to 3 weeks may be required for patients to normal-
ize the epidermal barrier function.
Androgen Excess Syndromes. Q13.4 For hirsutism and
recalcitrant acne vulgaris due to elevated adrenal androgens (most
commonly mild dehydroepiandrosterone-sulfate [DHEA-S] eleva-
tions), a unique CS approach is often indicated. In these patients,
night-time suppressive therapy with low-dose dexamethasone
(below physiologic dose levels) is predictably successful. Most cases
can be controlled with 0.125 to 0.375 mg of dexamethasone at
bedtime.57,58 This timing is important to suppress the early morn-
ing peak of ACTH, which stimulates adrenal androgen produc-
tion. A reasonable approach is to start with dexamethasone 0.125
mg nightly, with the repeat androgen laboratory test in 6 to 8
weeks. If the test result has not normalized, dose increases of 0.125
mg up to a maximum of 0.375 mg may be used, with follow-up
DHEA-S 6 to 8 weeks after dose increments. For a more complete
discussion on androgen excess syndromes, see Chapter 34. Addi-
tionally, short-term CS therapy can be considered to prevent acne
fulminans from flaring during initiation of isotretinoin for treat-
ment of severe nodulocystic acne.
Herpes Zoster/Postherpetic Neuralgia. Another controver-
sial area of systemic CS therapy is prevention of postherpetic neu-
ralgia. A 2013 Cochrane review concluded that systemic CS is
beneficial in treating acute pain related to herpes zoster infection,
but does not prevent postherpetic neuralgia.59 It is reasonable to
treat (1) patients with facial involvement, (2) patients with severe
acute pain during the cutaneous eruption, and (3) patients over
55 to 60 years of age, using combined antiviral and CS therapy,
ideally initially very early in the disease course. Although dissemi-
nated herpes zoster from CS therapy is a theoretical concern, this
is a distinctly uncommon complication in patients with normal
baseline immunity and simultaneous antiviral therapy. Recent evi-
dence suggests that systemic CS may have a greater role in treating
the acute pain of herpes zoster than for preventing postherpetic
neuralgia.60
Intramuscular Corticosteroid Administration
Background Issues. Q13.5 Dermatologists have long held
widely divergent viewpoints regarding the pros and cons of IM
CS therapy. Table 13.5 attempts to summarize both sides of the
‘argument.’ In addition, the relatively unique complications of IM
CS are listed in Box 13.4.
Hypothalamic-Pituitary-Adrenal-Axis Suppression. A pivotal
point of debate is the effect of IM CS on the HPA axis. Kusama and
associates detected HPA-axis suppression up to 3 to 4 weeks after
each injection of triamcinolone acetonide, as measured by plasma
cortisol and urine 17-hydroxycorticosteroids.61 Mikhail and col-
leagues studied patients receiving IM triamcinolone acetonide
every 6 weeks for 1.5 to 5 years.62 Roughly half the patients had
impaired response to the insulin hypoglycemia test. The authors
noted that the interval between doses is a more important factor
in HPA-axis suppression than the actual dose administered. Low-
dose IM CS at 2 to 4-week intervals produced greater suppression
than did higher doses at 6-week intervals. Using the metyrapone
test, Carson and associates found evidence of HPA-axis suppres-
sion up to 10 months after treatment.63 Droszcz and colleagues
detected abnormal ACTH stimulation in 6 of 48 patients (13%)
142 PA RT I V Systemic Immunomodulatory Drugs
• BOX 13.4 Complications Relatively Unique to
Intramuscular Corticosteroids61–62,118
Injection Site Complications
Cold abscess
Subcutaneous fat atrophy
Crystal deposition
Other Adverse Effects
Menstrual irregularities
Purpura (incidence appears to be increased)
receiving IM triamcinolone acetonide every 2 to 6 weeks.64 In a
related study, Carson and associates evaluated triamcinolone ace-
tonide 40 mg given every 3 weeks for four doses.63 This resulted
in anovulatory menstrual cycles in women because of decreased
gonadotropin levels. Traditionally it has been taught that CS-
induced menstrual abnormalities were generally due to IM CS.
More recently, relatively small studies have demonstrated that up
to 40% of premenopausal women on at least 20 mg prednisone
daily experience significant menstrual abnormalities.65
General Dosing Strategies. After the arguments and data just
given, a reasonably balanced viewpoint follows. Serious AE are
rare with either a single IM CS injection or a burst of oral pred-
nisone. Rarely do oral ‘bursts,’ single IM injections, or long-term
use of either route of administration result in clinically relevant,
significant HPA-axis suppression with CS use for dermatologic
indications. Neither route of administration has a clear-cut
advantage in withdrawal from chronic CS use. It is important to
focus on altering disease precipitators and providing adequately
aggressive topical therapy when either oral or IM CS are given.
Should repeated IM CS therapy be desired by clinicians, short-
to intermediate-acting products such as Celestone and Aristo-
cort should be used. When a long-acting form such as Kenalog
is used, a reasonable limit would be three to four injections per
year. Each clinician must make up his or her own mind concern-
ing the relative advantages and disadvantages of IM versus oral
CS therapy. As is often the case, the correct answer depends on
the clinical situation; neither form has a clear-cut advantage over
the other.
In general, the authors favors the precision of dosing and the
active patient participation that oral CS regimens require for most
dermatoses. Given the very thick stratum corneum on the palms
(and soles) and the general challenge of successfully treating vari-
ous subsets of hand dermatitis topically, our most common use of
IM CS is for these patients (Kenalog 80 mg IM ideally three to
four times yearly at most, ideally tapering to one to two injections
yearly over time).
Pulse Intravenous Corticosteroid Administration
General Philosophy and Dosing Strategies. Pulse CS therapy
has been proposed as a means to rapidly control life-threatening or
serious conditions with minimal toxicity, allowing for less aggres-
sive long-term maintenance CS therapy. Typically, 500 to 1000
mg of methylprednisolone (roughly 10–15 mg/kg daily) is given
IV over at least 60 minutes. This dose is repeated on a daily basis
for 3 to 5 consecutive days. Pulse methylprednisolone is tradi-
tionally administered in an inpatient setting, with cardiac and
electrolyte monitoring highly recommended. Alternate-day CS or
a nonsteroidal immunosuppressive (‘CS-sparing’) drug such aza-
thioprine and cyclosporine is used to maintain the improvement
from the pulse IV CS.
Risks of Pulse Intravenous Corticosteroid. Sudden death of
presumed cardiac origin is a notable complication of IV pulse CS
therapy.66,67 Atrial fibrillation has been reported as well.68 Fur-
thermore, anaphylaxis attributed to pulse IV CS is a potentially
life-threatening complication.69 Acute electrolyte shifts have been
postulated to explain the rare cases of sudden cardiac death.66,67
Careful potassium infusions may minimize the risk of these
potentially serious cardiac AE.70 Given that the vast majority of
cardiac complications have occurred outside of dermatologic set-
tings, some authors have questioned the need for hospitalization
and cardiac monitoring for dermatologic purposes.71 The recent
trend for pulse IV CS therapy is administration in an ambula-
tory setting if there is no significant renal or cardiac disease
present.
The suppression of various lymphocyte subsets is greater with
pulse CS therapy than with standard doses of oral CS therapy.72
CS-induced apoptosis likely plays a key role in this greater effect of
IV pulse CS therapy. In addition, there appears to be a persistent
decrease in natural killer cell activity. Other immunologic effects
are qualitatively similar to those of oral administration.
Summary. The overall interest in pulse CS therapy with IV
methylprednisolone has waned over the recent decades. This
modality should be used only when the severity of the patient’s
condition and the lack of response to alternative modes of therapy
indicate its appropriateness. Pulse IV methylprednisolone or dexa-
methasone therapy should be considered experimental and used
very selectively in an individualized fashion.
Adverse Effects
There is an imposing list of potential AE from the use of sys-
temic CS (Box 13.5). Brief bursts of CS for 2 to 3 weeks are sur-
prisingly safe and very useful in self-limiting dermatoses (Box
13.6). Q13.6 Lower-dose long-term regimens at or very near
replacement (physiologic) levels of CS also are reasonably safe.
Disease control and HPA-axis suppression are two key issues
that determine the rapidity of systemic CS dose tapering, and
HPA-axis suppression with the risk of CS withdrawal syndrome
is primarily an issue when dosing below ‘physiologic’ dose lev-
els. With supraphysiologic (pharmacologic) doses longer than 3
to 4 weeks there is an increased risk for more serious complica-
tions. The most serious AE come from relatively long-term use
at doses well above replacement (physiologic) levels. Patients
with bullous dermatoses, autoimmune connective tissue dis-
eases, vasculitis, and neutrophilic dermatoses all frequently need
such longer-term pharmacologic-level doses of CS. Cutaneous
AE and their proposed underlying mechanisms are listed in
Table 13.6.
General Points Regarding Tables for Adverse Effects.
Q13.7 Risk factors for CS AE and measures for prevention,
recognition, and management of important AE (Table 13.7)
are essential to understand, in order to maximize the safety of
prescribing systemic CS. The tables are not intended to be com-
prehensive; instead, the focus is on central issues relating to the
most important CS AE from the standpoint of magnitude of risk
and frequency of occurrence. The reviews footnoted as a basis
for these tables can provide further background information and
detailed references for interested readers.
 CHAPTER 13 Systemic Corticosteroids 143

• BOX 13.5 Important Adverse Effects of Systemic Corticosteroids by Category72–75,119

Hypothalamic-Pituitary-Adrenal Axis Psychiatric
Steroid withdrawal syndrome Psychosis
Addisonian crisis Agitation or personality change
Depression
Metabolic (Prednisone phobia or dependency)
Glucocorticoid effects
Hyperglycemia Neurologic
Increased appetite (and weight) Pseudotumor cerebri
Mineralocorticoid Effects (as a Result of Sodium Retention, Potassium Epidural lipomatosis
Loss) Peripheral neuropathy
Hypertension
Congestive heart failure Infectious
Excessive weight gain Tuberculosis reactivation
Hypokalemia Opportunistic—deep fungi, others
Lipid Effects (↑ Lipolysis and Altered Fat Deposition) Prolonged herpes virus infections
Hypertriglyceridemia
Cushingoid changes Muscular
Myopathy (with muscle atrophy)
Bone
Osteoporosis Pediatric
Osteonecrosis Growth impairment
Hypocalcemia (indirectly)
Cutaneous
Gastrointestinal See Table 13.6
Peptic ulcer disease
Bowel perforation Pulse Therapy
Fatty liver changes Electrolyte shifts
Esophageal reflux Cardiac dysrhythmias
Nausea, vomiting Seizures

Ocular Other
Cataracts ‘Opportunistic’ malignancies
Glaucoma Teratogenicity—doubtful
Infections especially staphylococcal Menstrual irregularity
Refraction changes (from corticosteroid-induced hyperglycemia)

• BOX 13.6 Common Adverse Effects with Prednisone
Bursts—in Absence of Relative
Contraindications
Metabolic
Increased appetite with weight gain
Fluid retention with edema and possibly weight gain
Psychiatric
Occasional patient may get ‘wired’ or ‘weird,’ especially if baseline
characteristics
Some patients may get depressed during tapering phase
Gastrointestinal
Mild gastroenteritis symptoms
Potentially Fatal Complications. It is most unusual to have a
fatal outcome when CS is prescribed for dermatologic indications.
Drug-induced fatalities in older studies of CS (with or without
other immunosuppressive agents) for pemphigus vulgaris are a
noteworthy exception of historical significance. Q13.8 Table
13.8 provides relevant references for the AE of systemic CS that
have even a remote potential for a fatal outcome. A few points are
highlighted for each of these AE below:
• Adrenal crisis (Addisonian crisis)—In the current era this
complication is extraordinarily rare. When in doubt, clinicians
should err on the side of prescribing ‘stress CS doses’ when
indicated.13,73–75
• Bowel perforation—Exercise tremendous caution with the use
of systemic CS after recent bowel anastomosis and for patients
with active diverticulitis.76,77
• Peptic ulcer perforation—This complication is most likely with
adjunctive nonsteroidal anti-inflammatory drugs (NSAID) and
patients with a history of peptic ulcer disease (PUD). Albeit
controversial, proactive use of H2 antagonists or proton pump
inhibitors for patients with prior history of PUD and for
patients with symptoms even possibly related to PUD is sug-
gested.78–80
• Pancreatitis—This complication largely occurs with an acute
elevation of triglycerides greater than 800 mg/dL. The clinician
should intervene promptly with any reports of severe abdomi-
nal pain with systemic CS use.81–84
• Severe hyperglycemia (diabetic ketoacidosis or hyperosmo-
lar nonketotic coma)—Although occasionally this may occur
de novo, most severe hyperglycemia occurs with pre-existing
diabetes mellitus. The widespread availability of home glucose
monitoring should make this a rare complication.85,86
144 PA RT I V Systemic Immunomodulatory Drugs
TABLE
13.6 Cutaneous Adverse Effects From Systemic Corticosteroids13,63,119
Category Mechanism
Wound healing and related changes ↓ Collagen, ground substance;
↓ Re-epithelialization, angiogenesis
Pilosebaceous Pityrosporum ovale, androgenicity
Vascular Catabolic effects on vascular smooth muscle
Cutaneous infections See Table 7.3
Hair effects Uncertain for telogen effluvium
Injectable CS Lipolysis of subcutaneous fat
Other skin effects ↓ CS immunosuppression (taper)
Insulin resistance
CS, Corticosteroid.
• Opportunistic infections—These infections are distinctly
uncommon with CS used for dermatologic indications, and
occur primarily with multidrug immunosuppression regimens
for systemic autoimmune disorders and for organ transplanta-
tion.87–92 The relative risk (RR) of tuberculosis is 7.7 (confi-
dence interval [CI] 2.8–21.4) for prednisone doses of at least
15 mg daily, whereas at doses less than 15 mg daily the RR
barely reaches significance (RR 2.8; CI 1.0–7.9). Immunosup-
pressive therapy (CS, other) significantly reduces purified pro-
tein derivative (PPD) screening reactivity. Although not ideal,
interferon (IFN)-γ release assays (various names) are more reli-
able than a PPD in the presence of immunosuppressive ther-
apy, including with CS therapy. Baseline screening for hepatitis
B, hepatitis C, and human immunodeficiency virus (HIV)
should also be strongly considered. Additionally, prophylaxis
for pneumocystis pneumonia and strongyloides infections can
be considered in at-risk populations.93
• Immunosuppression carcinogenesis (‘Opportunistic malig-
nancies’ denotes Kaposi sarcoma, non-Hodgkin lymphoma,
squamous cell carcinoma, and Merkel cell carcinoma that are
common in solid organ transplantation patients)—Likewise
this complication is very uncommon with systemic CS for
purely dermatologic indications.13,94
Pregnancy Risk. Several older studies have demonstrated
increased teratogenesis in laboratory animals as a result of CS
therapy. Cleft lip and palate are the most common specific mal-
formations. Multiple studies in humans concerning patients with
CS-dependent systemic conditions during pregnancy have dem-
onstrated no significantly increased risk of congenital malforma-
tions in humans.95 In general, these studies have evaluated the
use of CS for conditions in which there is a major maternal risk if
systemic CS is withheld during pregnancy. These studies that doc-
umented no increased risk of teratogenicity include patients with
systemic lupus erythematosus (SLE) and related autoimmune
connective tissue diseases,96,97 severe asthma,98–100 and organ
transplantation.101 As with any drug in pregnancy, CS should be
used only when the drug is clearly indicated, and if the potential
benefits far exceed the potential risk to the mother and fetus.
Fetal HPA-axis suppression is important to consider, particu-
larly when CS therapy is used near the time of delivery. There may
be an increased risk of stillbirth and spontaneous abortion.72
Adverse Effects
Nonhealing wounds, ulcers, striae, atrophy, telangi-
ectasias
‘Steroid acne,’ ‘steroid rosacea’
Purpura, including actinic purpura
Staphylococcal, herpes virus infections in particular
Telogen effluvium, hirsutism
Fat atrophy; crystallization of injectable material
Pustular psoriasis flare, rebound of poison ivy/oak
Acanthosis nigricans
Other Adverse Effects with the Potential for Serious Mor-
bidity. Q13.7 A number of potentially serious complications
of systemic CS (as well as adrenal crisis and immunosuppres-
sion carcinogenesis, discussed earlier) have been reviewed.13 This
monograph included thorough reviews of the following important
potential CS complications:
• Osteonecrosis (avascular necrosis, aseptic necrosis)—Brief
bursts of systemic CS simply do not create a true risk for
osteonecrosis. The medicolegal implications of this concept
are very important. The vast majority of osteonecrosis cases
in the literature are with pharmacologic doses of prednisone
(or comparable doses of other systemic CS) for at least 2 to 3
months continuously for life-threatening conditions. There is
no doubt that long-term (at least 3 months) continuous CS
therapy increases the risk of osteonecrosis, with the greatest
risk in SLE patients.13 The author (SEW) reviewed all studies
with at least 100 patients on long-term CS for either SLE or
renal transplantation; in a total of 39 studies, only two studies
had even one patient develop osteonecrosis before 3 months
of continuous CS therapy. Given the relative frequency of CS
prescriptions (see earlier) and idiopathic osteonecrosis (≤30%
of all cases), it is reasonable to speculate that the great majority
(if not all) reports of osteonecrosis from CS bursts are because
of chance overlap.
• Osteoporosis—Preventive measures to retard the expected CS-
induced bone calcium depletion for any patient receiving phar-
macologic doses of CS for at least 1 month are imperative. The
hierarchy of options includes calcium (1000–1500 mg daily),
vitamin D (800 U daily), bisphosphonates, teriparatide, and
nasal calcitonin. Bone density assessment with dual energy
x-ray absorptiometry (‘DEXA’) scans has revolutionized the
surveillance for this important complication. The great major-
ity of CS AE are minimized by doses with chronic doses at or
below physiologic range (5–7.5 mg of prednisone on a daily
basis). In contrast, there is a significant risk of CS-induced
osteoporotic fractures with prednisone doses between 2.5 and
5 mg daily; therefore, clinicians should be proactive with phar-
macologic measures to prevent osteoporosis (calcium, vitamin
D, and ideally bisphosphonates) even in this dose range. CS
therapy has been ‘attributed’ to induce 47% of all hip fractures
and 72% of all vertebral fractures.
TABLE
13.7 Overview of Selected Corticosteroid Adverse Effects13,19,20,63,93,102,120–122

Adverse Proposed
Effect Mechanisms CS Therapy Factors Additional Risk Factors Preventiona Diagnosis Management
HPA-Axis Effects
Adrenal Reduced GC and MC Abrupt cessation of Major surgery, trauma, or illness; ‘Stress dose’ CS (see History (see text) Fluids and
crisis reserves—normally CS (in addition to severe gastroenteritis with fluid text) glucocorticoid
there are adequate major stressors) and electrolyte loss replacement
compensatory in patients on >20
mechanisms for GC mg daily for >3
and MC effects such weeks
that major complica-
tions are very rare in
dermatologic therapy
CS with- Reduced GC and MC Abrupt CS tapering None Appropriate CS tapering History (see text) Raise CS dose,
drawal with intermediate then taper
syndrome and chronic dura- much more
tion therapy slowly

Metabolic Effects
Hyperglyce- GC effects—↑ hepatic Especially with high Family or personal history of DM, Dietary measures, rec- Fasting glucose levels ADA diet, insulin,
mia glucose/glyco- CS dose obesity; rarely de novo DM ommend glucometer OHGA, insulin
gen production, ↑ development (is generally revers- sensitizers, etc.
gluconeogenesis via ible); traditional risk factors are
protein catabolism, less often present in medication-
induce insulin induced diabetes
resistance producing
↓ glucose entry into
cells

CHAPTER 13
Hypertension MC effects—sodium CS with high MC Prior hypertension, elderly patients; Sodium restriction, Monitor blood pres- Initially sodium
retention; also in part effect, therapy rarely occurs with bursts of CS choose CS with low sure; usually mild restriction, thia-
due to GC-induced over 1 year, pulse MC effect elevation zide diuretic
vasoconstriction CS

Systemic Corticosteroids
Congestive MC effects—↑ sodium CS with high MC Prior well- or partially compensated Sodium restriction, History, examination, Initially sodium
heart retention, resultant effect CHF choose CS with low weights restriction, thia-
failure fluid overload in pre- MC effect zide diuretic
disposed individuals
Hyperlipid- GC effects—overall Especially with high Caloric/saturated fat excesses, Low-calorie, low- Triglyceridesb (milder Gemfibrozil,
emia result of catabolic CS dose personal or family history of saturated fat diet cholesterol eleva- ‘statins’
state, in part initiated hyperlipidemia, DM, hypothyroid- tions)
by ↑ lipoprotein lipase ism

Continued

145
 146
TABLE
13.7 Overview of Selected Corticosteroid Adverse Effects13,19,20,63,93,102,120–122—cont’d

PART IV
Adverse Proposed
Effect Mechanisms CS Therapy Factors Additional Risk Factors Preventiona Diagnosis Management
Cushingoid Altered fat distribution, CS for at least 2–3 Excessive caloric intake because of Dietary measures, Examination, weights Low-calorie diet,
changes uncertain mecha- months increased appetite exercise exercise
nism; result of overall

Systemic Immunomodulatory Drugs

fat catabolism

Bone Effects
Growth As a result of ↓ growth Chronic pharma- Transplantation or autoimmune Low single AM dose of Plotting height and If possible taper
impair- hormone and IGF-1 cologic dose CS condition in children requiring CS; QOD also helpful weight on growth CS; possibly
ment production; net result therapy, ↓↓ with indefinite CS therapy chart in children growth hor-
delayed skeletal QOD mone
maturation
Osteoporo- ↑ Osteoclast activity, ↓ No decrease with Female gender, increased age, Calcium 1200 mg and Serial bone densi- Strongly consider
sisc osteoblast activ- QOD CS thin, inactive patients, previ- vitamin D 800 IU, tometry (annually bisphospho-
ity, ↓ GI absorption ous fracture, smoking, alcohol physical activity or based on risk), nates; also
of calcium, ↑ renal use, history of falls, vitamin D abnormal T score nasal calcitonin,
excretion of calcium; deficiency at highest risk; men at <–2.5; consider teriparatide
resultant secondary risk as well (overall highest risk ‘baseline’ by 1–2
hyperparathyroidism of bone loss in young men) months
and bone resorption
Osteonecro- ↑ Marrow fat deposi- Continuous, pharma- Significant trauma, smoking, alcohol Avoidance trauma, Focal pain in hip, Prompt referral,
sis tion, compression of cologic CS for at abuse, hypercoagulable condi- alcohol excess, shoulder or knee; core decom-
interosseous vessels; least 2–3 months tions, hyperlipidemia smoking MRI scan is the pression, joint
hypercoagulability As definitive test replacement
a result of endog-
enous disorders or
exogenous factors
such as smoking,
alcohol, trauma

Gi Effects
Bowel perfo- GC catabolic effects Dose, duration of CS Recent bowel anastomosis, active Caution with CS after CS may mask signs Prompt surgical
ration producing ↓ wound not a key determi- diverticulitis bowel surgery and symptoms of referral
healing after recent nant of risk perforation
bowel anastomosis
Peptic ulcer ↓ Mucus production, ↑ Total CS dose of 1g Concomitant ASA, NSAID therapy, H2 antihistamines in History; upper GI H2 antihistamines,
disease acid production; CS age >65 years, smoking, alcohol, higher-risk patients endoscopy proton pump
(PUD) not a direct gastric history of PUD, Helicobacter inhibitors
irritant pylori or autoimmune connective
tissue disease
TABLE
13.7 Overview of Selected Corticosteroid Adverse Effects13,19,20,63,93,102,120–122—cont’d

Adverse Proposed
Effect Mechanisms CS Therapy Factors Additional Risk Factors Preventiona Diagnosis Management
Other Adverse Effects
Cataracts Altered lens proteins, No decrease with Baseline lens opacities, older Sunglasses may help Slit-lamp examination If advanced, cata-
with uncertain QOD CS patients, children every 6–12 months ract removal
mechanism (typically and lens
posterior subcap- implant
sular)
Agitation/ Possibly because of CS at least 40 mg/ Family history of psychosis, baseline Careful patient selec- History; depression Doxepin (if agita-
psychosis electrolyte shifts, day; doses above high anxiety, female gender tion if prior psychiat- may occur during tion); may need
altered nerve excit- 80 mg/day high (especially day 15–30 of CS ric disorder tapering lithium (found
ability, possibly mild risk course) effective for
cerebral edema prophylaxis and
management)
or antipsychot-
ics12,7
Opportunistic Impaired immunologic Prolonged high CS Multidrug immunosuppression Pretreatment testing High index of Varies
infections responses—see dose; ↓↓ risk with therapy, transplantation patients (HIV, hepatitis B, suspicion (may
Table 13.2 QOD. CS with ‘foreign’ antigen present hepatitis C, TB) and not manifest
long-term. High-risk dermatology vaccinations includ- symptoms of infec-
population includes patients with ing VZV in patients tion as clearly as
SLE, dermatomyositis, or immu- age >50–60 years); immunocompetent
nobullous disease on another Pneumocystis pneu- patients); consider
immunosuppressive agent or monia prophylaxis strongyloides
who have a history of hemato- with TMP-SMX DS screening with
logic malignancy or interstitial 160/800 mg TIW or IgG antibodies
lung disease dapsone 100 mg in patients with
daily peripheral eosino-
philia in endemic

CHAPTER 13
areas

Myopathy ↓ Glucose and amino Fluorinated CS, rapid Lack of exercise Exercise, caution with Proximal muscle Gradual taper of
acid uptake by CS taper CS tapering after weakness, may CS dose; exer-
muscles, leading high-dose therapy have pain; muscle cise especially
to muscle atrophy/ enzymes often if muscle atro-

Systemic Corticosteroids
wasting normal phy/wasting
aIneach of the above adverse effects, careful dosing is important for prevention; anticipate high-risk patients.
bParticularcaution should be exercised with triglyceride levels over 400–500 mg/dL; risk of pancreatitis becomes significant with levels above 800 mg/dL.
cGreatest CS effect on bone resorption at sites of high trabecular bone content such as ribs, vertebral bodies and flat bones of pelvis—correspond to sites with greatest risk of fractures.

ADA, American Diabetes Association; CHF, congestive heart failure; CS, corticosteroid; DM, diabetes mellitus; GC, glucocorticoid; GI, gastrointestinal; HPA, hypothalamic-pituitary-adrenal; IGF-1, insulin-like growth factor 1; IgG, immunoglobulin G; MC, mineralocorticoid;
MRI, magnetic resonance imaging; NSAID, nonsteroidal anti-inflammatory drug; OHGA, oral hypoglycemic agent; TB, tuberculosis; TMP-SMX DS, trimethoprim-sulfamethoxazole double strengthL; VZV, varicella zoster virus.

147
148 PA RT I V Systemic Immunomodulatory Drugs
TABLE
13.8 Corticosteroid Complications That May Rarely Be Fatal
Complication
Adrenal crisis8,64,102
Bowel perforation76–78
Perforated PUD79,80
Pancreatitis81–84
Severe hyperglycemia85,86
Opportunistic infectionsa 87–93
‘Opportunistic’ malignanciesb 13,94
aOpportunistic infections occasionally present in patients receiving CS for inflammatory or autoimmune conditions include infections caused by candidiasis (unusual locations), cryptococcosis, aspergillosis,
listeriosis, herpes virus (widespread), cytomegalovirus, Pneumocystis jiroveckii, and strongyloidiasis.
b’Opportunistic’ in this case refers to predominantly viral-induced malignancies, which are markedly increased with multidrug immunosuppression regimens most commonly used in transplantation set-
ting—especially non-Hodgkin lymphomas, Kaposi sarcoma, Merkel cell carcinoma, and cutaneous/female genitourinary tract squamous cell carcinomas.
ASA, Aspirin; CS, corticosteroid; NSAID, nonsteroidal anti-inflammatory drug; PUD, peptic ulcer disease.
• Growth impairment in children—This is rarely an issue for
dermatologic indications. Even with CS use in transplanta-
tion settings and for serious systemic autoimmune conditions
in children, catch-up growth is possible when CS are reduced
to physiologic levels or below. Attempt to wean CS as soon as
possible in pediatric patients and consider referral to a pedi-
atric endocrinologist for any patient who requires ongoing or
repeated doses of CS for disease management.
Miscellaneous Noteworthy Adverse Effects.
• Lipodystrophy and related metabolic syndrome changes—
Up to 66% of patients on long-term therapy of at least 20
mg of prednisone daily have lipodystrophy, including moon
face, ‘buffalo hump,’ and central obesity. The lipodystro-
phy is associated with increased risk of metabolic syndrome
(increased body mass index, hypertension, hyperlipidemia,
hyperglycemia), with resultant increased cardiovascular dis-
ease risk. This abnormality is the most distressing aspect of
CS therapy to patients, possibly affecting compliance. Pred-
nisone doses <10 mg daily will generally allow at least par-
tial reversal of the lipodystrophy.
• High frequency of mood and thought disorders—Up to
30% of patients on short-term CS therapy develop hypo-
mania and sleep disorders early in the course. Up to 10%
of patients on short-term CS therapy develop significant
depression, often during CS taper. Psychosis occurs roughly
twice as often in CS-treated patients as in controls. It is the
authors’ observation that patients who at baseline are ‘wired’
(risk hypomania) or ‘weird’ (risk CS psychosis, ‘personality
change’) are at risk for CS-induced mood and thought dis-
orders.
Comments
Distinctly uncommon currently perhaps because of heightened awareness, aggressive emergency room, or
postoperative preventive and therapeutic measures
Best treatment is prevention; can have catastrophic outcome if late diagnosis
Typically factors such as ASA or NSAID, known history of PUD present, heavy tobacco or alcohol use,
patients >65 years of age, and patients taking other medications that increase risk such as bisphospho-
nates; gastric ulcers and perforation more common than duodenal
Primarily a result of triglyceride elevations >800 mg/dL, typically occurs in the first 2–4 weeks of therapy;
possible role of increased viscosity of pancreatic secretions leading to obstruction
Risk primarily if diabetic ketoacidosis or hyperosmolar nonketotic coma results; overall these complications
are rare, perhaps due in part to home glucose monitoring
Strikingly uncommon in dermatologic therapy, at-risk groups include patients with systemic lupus erythe-
matosus, dermatomyositis, or immunobullous disease on ≥1 additional immunosuppressive agent in
addition to CS and have other serious comorbidities including malignancy or interstitial lung disease;
greater risk with multidrug immunosuppressive regimens common with organ transplantation
Primarily with CS in multidrug immunosuppression regimens in transplantation settings; Kaposi sarcoma
may be an exception with CS use alone
Hypothalamic-Pituitary-Adrenal-Axis
Suppression
Adrenal Insufficiency—Definitions. It is important to have
a clear set of definitions for the various types of adrenal insuf-
ficiency. The three categories of adrenal insufficiency are listed in
Table 13.9.15,19 In order for the patient to present with Addison-
like symptoms, more than 90% of the cortisol-producing zona fas-
ciculata must be destroyed, reflecting the inherent reserve capacity
of the adrenal gland. Note that significant MC reduction (risk for
fluid and electrolyte abnormalities) and increased ACTH produc-
tion (with hyperpigmentation) are noted only in primary adrenal
insufficiency. Furthermore, only in secondary endogenous adrenal
insufficiency is there reduction of other tropic hormones, such
as the gonadotropins (luteinizing hormone, follicle-stimulating
hormone), growth hormone, and thyroid-stimulating hormone.
The most important type of adrenal insufficiency for derma-
tologists to understand is the secondary exogenous type, typically
because of pharmacologic doses of systemic CS therapy for at least
3 to 4 weeks.12,14 There is striking individual variability in suscep-
tibility to secondary exogenous adrenal insufficiency. In patients
with secondary exogenous adrenal insufficiency there are (1) no
significant MC abnormalities, (2) no increased ACTH produc-
tion, and (3) no pituitary tropic hormone abnormalities.
Hypothalamic-Pituitary-Adrenal-Axis Suppression—Over-
view. It is important to consider the HPA axis as a unit, rather
than to simply focus on the adrenal gland.13 Q13.9 This is
because of the importance of the entire HPA axis in stress
responses. The hypothalamus is not only the site most susceptible
to drug-induced suppression, but is also the quickest to recover

TABLE
13.9 Major Categories of Adrenal Insufficiency11,12
Category Etiologies
Primary Addison disease
Secondary—endogenous Usually neoplasms of pituitary
Secondary—exogenous Prolonged, high-dose CS therapy
aWhen MC levels are reduced, the patient is at risk for severe hypotension and electrolyte abnormalities; if the levels are normal, fluid/electrolyte abnormalities are not a key component of this type of
adrenal insufficiency, such as with corticosteroid therapy.
bWhen ACTH levels are increased, there is a stimulatory effect on melanocytes resulting in hyperpigmentation characteristic of Addison disease.
ACTH, Adrenocorticotropic hormone; MC, mineralocorticoid.
after cessation of therapy. This relatively prompt recovery occurs
in most clinical scenarios within 14 to 30 days after cessation of
CS therapy. The adrenal gland is more resistant to suppression
and, likewise, is slower to recover once CS therapy is stopped.
Overall, the hypothalamus is the most important part of the axis
in terms of stress responsiveness.
The susceptibility to HPA-axis suppression is a function of both
the dose and the duration of CS therapy.13,102 Doses significantly
exceeding physiologic levels for at least 3 to 4 weeks can produce
clinically relevant mild HPA-axis suppression. Divided-dose regi-
mens and single-dose therapy given at a time other than morning
will increase the risk of HPA-axis suppression. Finally, the longer-
acting CS preparations are more likely to produce HPA-axis sup-
pression than are short- and intermediate-duration CS.
Laboratory-detectable suppression may occur within days of
moderate- to high-dose therapy.13 This suppression is short-lived
and of little clinical importance. Significant HPA-axis suppres-
sion with physiologic (replacement) doses of CS for a prolonged
duration is distinctly uncommon. With long-term, high-dose
CS therapy, morning cortisol levels may generally require 6 to 9
months or more to return to normal limits. Some authors report
a period of up to 12 to 16 months of increased vulnerability to
stress, which is based on impaired ACTH stimulation test produc-
tion of cortisol.
There is only slight blunting of HPA-axis responsiveness with
off-day testing during prolonged alternate-day therapy. Even
though alternate-day therapy lessens the risk of HPA-axis suppres-
sion, it does not speed the recovery once this suppression occurs.
Pulsatile administration of CRF has been shown to speed the rate
of recovery from HPA-axis suppression.
Alternate Means of Stress Responsiveness. (See Box 13.2
HPA axis in a nutshell)
Q13.10 The direct CS effect in producing elevated blood
glucose is much slower than the catecholamine response. Both
ACTH and cortisol can indirectly induce rapid glucose elevation
through release of epinephrine.13,14
The MC aldosterone does not play a significant role in the
HPA-axis stress response. Of importance is that secondary exog-
enous adrenal insufficiency from CS therapy typically leaves MC
production intact. Thus, the risk of hypotension and electrolyte
abnormalities is relatively low. In addition, through direct and/or
indirect catecholamine, acetylcholine, vasopressin, and serotonin
effects, blood glucose responses generally remain intact. Finally,
the response of the hypothalamus to stress is typically reversible
over 2 to 4 weeks, which makes prolonged supplementation with
‘stress doses’ of CS overall unnecessary.
CHAPTER 13 Systemic Corticosteroids 149
MC Levels ACTH Levels Pituitary Findings
Reduceda Increasedb No other pituitary findings
Normal Normal Other pituitary tropic hormones
also reduced
Normal Normal No other pituitary findings
Laboratory Tests of Hypothalamic-Pituitary-Adrenal-Axis
Function. These tests are uncommonly used in dermatologic prac-
tice. Nevertheless, clinicians in all fields should be familiar with
the various tests used, including the strengths and limitations of
each. In particular, clinicians should know (1) whether a given test
reflects function of the entire axis, or (2) only evaluates one partic-
ular organ, such as the adrenal gland. In addition, it is important
whether the test performed examines basal function versus stress
responsiveness (Table 13.10).
The primary test of basal HPA-axis function is that of the
morning cortisol level.15,103–105 The normal peak cortisol value
occurs around 8:00 AM, and the trough value occurs in the late
afternoon. Current radioimmunoassay techniques are minimally
altered by exogenous prednisone, prednisolone, and dexametha-
sone therapy. Nevertheless, it is generally recommended to omit
the morning CS dose on the day that the cortisol level is checked.
Cortisol levels generally range from 5 to 30 mg/dL, with levels
up to 60 mg/dL with physical stressors. With prolonged therapy,
morning cortisol levels less than 10 mg/dL suggest impaired basal
HPA-axis function.
The reader is referred to several reviews of HPA-axis testing for
further details for tests listed in Table 13.10. In general, endocri-
nology consultation is required for tests other than basal testing of
morning cortisol levels. It is important to reiterate here that the
commonly used ACTH stimulation test does not reflect the func-
tion of the entire HPA axis. Many physicians, despite a normal
ACTH stimulation test, still supplement the patients with ‘stress
doses’ of CS. This practice limits the value of the ACTH test, and
the morning cortisol alone may be sufficient to at least ascertain
adequate basal HPA-axis function.
Adrenal Crisis and Corticosteroid Withdrawal Syndrome.
Given the millions of patients who have received systemic CS
therapy since the 1950s, there is a striking paucity of well-doc-
umented cases of death because of acute Addisonian crisis.8,73–75
Such patients exhibit (1) characteristic symptoms of adrenal insuf-
ficiency, (2) hypotension, and (3) markedly decreased cortisol
levels, in the absence of alternative explanations for these find-
ings (Table 13.11). Q13.10 In general, momentous stressors are
required to produce vascular collapse because of secondary exog-
enous adrenal insufficiency. The paucity of serious outcomes is
largely explained by the preservation of MC function in (drug-
induced) secondary exogenous adrenal insufficiency. Alternative
nonsteroidal mechanisms of stress response discussed previously
also help assure sodium and glucose homeostasis in these settings.
Q13.6 Given its much greater incidence, dermatologists
should be familiar with a condition known as CS withdrawal
150 PA RT I V Systemic Immunomodulatory Drugs

TABLE 11,102–105
13.10 Primary Tests Used to Evaluate Adrenal Insufficiency

Test Name Basal vs Stress Part of HPA Axis Tested How Test Performed Comments
AM cortisol Basal Adrenal gland Check 8:00 AM serum cortisol Ideally omit CS dose until
level after testing
Twenty-four hour urine Basal Adrenal gland Simple 24-hour urine collection, More expensive, more
free cortisol check free cortisol levels precise test basal
status
ACTH stimulation Stress Adrenal gland Check basal, 30-minute and Most commonly used
60-minute cortisol levels provocative test
after ACTHa injection
Insulin hypoglycemiab Stress Entire HPA axis Levels of cortisol checked after Must have normal ACTH
insulin injection stimulation test first
Metyraponeb Stress Entire HPA axis 11-Deoxycortisol levels Must have normal ACTH
measured after metyrapone stimulation test first
injection

Corticotropin-releasing Stress Entire HPA axis Level of cortisol checked after Very expensive; perhaps
factor (CRF)b CRF injection best test of entire axis
aThe ACTH form injected Cosyntropin (IM or IV) using a 250 μg dose after baseline cortisol determination.
bThese tests are cumbersome, have some inherent risk, and require endocrine consultation; the counterpoint is that these are the only tests above which evaluate function of the entire HPA axis under
‘stressful’ conditions.
ACTH, Adrenocorticotropic hormone; CS, corticosteroid; HPA, hypothalamic-pituitary-adrenal; IM, intramuscular; IV, intravenous.

TABLE
13.11 Comparison of ‘Steroid Withdrawal Syndrome’ Versus ‘Adrenal Crisis’ Clinical Findings10,102,107,108

Stage and Category Clinical Findings

Steroid Withdrawal Syndrome—Mild To Moderate Severity
General findings Fatigue, lethargy, malaise
Neuropsychiatric findings Depression, mood swings, headache (a.m.)
Musculoskeletal findings Myalgias, arthralgias, flu-like symptoms

Steroid Withdrawal Syndrome—More Severe

Gastrointestinal findings Anorexia, nausea, vomiting, weight loss

Adrenal (Addisonian) Crisis (above findings plus the following)

Glucocorticoid deficiencya Hypoglycemia, although glucose values may be normal

Mineralocorticoid deficiencyb Hypotension (including postural), shock, decreased consciousness, seizure,

hyperkalemia, sodium depletion (may have normal sodium serum levels
in spite of total body sodium depletion)
aFor comments on multiple compensatory mechanisms the body uses to preserve serum glucose levels, see text.
bAldosterone production is intact with CS-induced secondary exogenous adrenal insufficiency; there is some MC effect reduction with ↓ endogenous cortisol levels or with abrupt tapering of exogenous
CS (typically prednisone).
CS, Corticosteroid; MC, mineralocorticoid.

syndrome (SWS).15,106 In patients with SWS, there is no signifi-
cant change in the serum cortisol level. However, it is postulated
that there may be a sudden decrease in CS available at the cellular
level. There is evidence to suggest that IL-6 (and to a lesser extent
IL-1β and TNF-α) is responsible for much of the symptomatol-
ogy associated with SWS.107
SWS is precipitated by abrupt CS tapering with intermedi-
ate- and chronic duration therapy. With rapid tapering of phar-
macologic doses beyond 2 to 3 weeks it is possible to develop
SWS. Presenting signs and symptoms include (1) arthralgias and
myalgias, (2) mood swings, (3) headache, (4) fatigue and lethargy,
and (5) in severe cases, anorexia, nausea, and vomiting. The return
to higher CS doses (last dose that preceded the SWS clinical pre-
sentation, with more gradual subsequent CS tapering) will typi-
cally promptly eliminate these symptoms.
Stress Corticosteroid Doses—Historical Perspective.
The question of stress CS doses arises primarily with surgery
performed on patients who have received prolonged pharma-
cologic doses of CS therapy. Owing to the effects of anesthe-
sia, surgical trauma, or both, most major surgical procedures

stimulate a rise in endogenous cortisol production.14,15 The
regimens are based on the rise of basal cortisol production of
about 25 mg daily to a maximum of 250 mg daily with major
physical stressors. Historically, the IV form of hydrocortisone
(Solu-Cortef ) is administered at a dose of 100 mg the night
before surgery, perioperatively, and every 8 hours on the day of
surgery. The dose is reduced by 50% daily until the previous
CS dose is reached. Although the risk associated with these
‘stress doses’ is low, supplementing patients during major sur-
gery beyond 1 to 2 months following cessation of CS therapy
may be unnecessary. Major infections, trauma, and myocardial
infarction may require stress doses, as outlined earlier.
Minor physical stresses, such as febrile illnesses, can be supple-
mented at a dose level twice the basal production of endogenous
CS. This amount is rapidly tapered back to the dose the patient
was taking before the ‘stressful’ event. This minor stress supple-
mentation is required only for patients taking less than 15 to 20
mg of prednisone per day.
Stress Corticosteroid Doses—Newer Perspective. The
more traditional approaches described in the previous section
have recently been challenged by a variety of authors.108–111
These authors cite data suggesting that replacement doses of
systemic CS may suffice for surgical ‘stress’ and for other non-
surgical physiologic stressors. Perioperative adrenal insufficiency
is rare (<0.1%) and the ACTH stimulation test too sensitive as
a predictor. A systematic review noting no perioperative hemo-
dynamic compromise in two randomized controlled trials in the
absence of CS ‘stress doses’ is reassuring.112 In five cohort stud-
ies, only two patients had perioperative adrenal insufficiency;
the patients did not take their CS dose for 36 and 48 hours pre-
operatively, respectively.112 In the absence of primary (adrenal)
or secondary (hypothalamus, pituitary) adrenal insufficiency,
perioperative patients simply need to take their daily current
maintenance dose of CS when receiving long-term systemic CS.
Drug Interactions
Table 13.12 lists the clinically relevant drug interactions involving
systemic CS. There are a relatively small number of potentially
serious drug interactions, with very few involving prednisone or
prednisolone. The majority of interactions are caused by dexa-
methasone and methylprednisolone.
Monitoring Guidelines
Compared with virtually all other systemic drugs with monitoring
guidelines in this book, it is relatively challenging to propose a
set of monitoring guidelines for systemic CS (Box 13.7 and Table
13.13). Q13.6 Given that there is a paucity of previously pub-
lished guidelines, the more important reason is that the dosing
strategy for systemic CS is more of an ‘attack, retreat’ mentality,
such that doses above physiologic levels for longer than 1 to 2
months should be uncommon. Most of the patients who would
have historically required sustained moderate- to high-dose CS in
the past should now be on reasonably aggressive courses of nonste-
roidal immunosuppressive (CS-sparing) drugs, in order to allow
tapering of the CS to physiologic levels if at all possible. For the
relatively small percentage of patients with CS doses at or above
physiologic levels for many months, these guidelines should be
of significant value. In particular, DEXA scans, blood pressure
screening, and laboratory tests for metabolic abnormalities are of
central importance.
CHAPTER 13 Systemic Corticosteroids 151
Therapeutic Guidelines
Individualized Risk–Benefit Analysis. Q13.11 Any deci-
sion to use CS can always be simplified to a risk–benefit analysis.
The risks in the equation are specifically the risks of CS for that
particular patient. This includes any contraindications or risk fac-
tors that put the patient at increased risk for a specific AE. The
anticipated dose and duration of CS therapy are very important in
determining these risks.
The benefits of CS therapy are accomplished through the
reduction or eradication of the potential risks of the disease to be
treated. The inherent severity and natural history of the disease, as
well as the ability of CS to alter this natural history, are central to
the risk–benefit decision. CS therapy is optimal (benefit:risk ratio)
when the disease can be suppressed quickly with minimal risk for
toxicity (owing to the absence of relative contraindications or risk
factors).
In brief, the decision resolves around whether the CS therapy
can be given (1) soon enough, (2) at high-enough doses, and
(3) for a long-enough duration to obtain the desired benefits. This
is balanced by whether the therapy can be administered at a low-
enough dose and for a short-enough duration to minimize the
risks. Box 13.8 summarizes important principles to maximize the
overall safety of systemic CS therapy.
Acute Dosage Options. Q13.6 Most CS therapy is given as a
single oral daily dose in the morning with an intermediate-dura-
tion CS such as prednisone. This method most closely approxi-
mates the body’s own diurnal variation of cortisol production.
Divided doses, typically given twice daily, are reserved for acute
therapy for severe, potentially life-threatening illnesses such as
pemphigus vulgaris. Administration of CS four times daily gen-
erally uses IV methylprednisolone in ‘high-dose’ (up to 2–2.5
mg/kg daily; but not at doses used in ‘pulse’ therapy) therapy for
selected patients with early SJS. When a constant total daily dose
is given, divided-dose regimens have greater therapeutic benefits
than equivalent daily-dose regimens; in addition, divided-dose
regimens produce a greater risk of AE than a comparable dose give
as a single daily dose.
The briefer the duration for which CS therapy exceeds physi-
ologic doses, the lower the risk of significant AE. Brief bursts (2–3
weeks or less), intermediate duration (over 3–4 weeks, up to per-
haps 3–4 months at most), and chronic therapy (indefinite) are
the key options regarding therapeutic duration.
Q13.2 Physiologic (replacement) CS therapy is 5 to 7.5 mg
daily of prednisone or its equivalent; physiologic doses for all CS
therapies are listed in Table 13.1. Pharmacologic dosage ranges at
the initiation of therapy include high dose (>60 mg daily), mod-
erate-dose (40–60 mg daily), and low-dose (<40 mg daily) CS
therapy. Apart from potentially life-threatening dermatoses such
as pemphigus vulgaris and bullous pemphigoid, most dermato-
logic conditions can be controlled by moderate- to low-dosage
regimens. It is important to determine initially how the disease
activity will be followed. Upon achieving a desired outcome the
patient will conclude the acute phase of therapy, and the tapering
principles described later in this section should be followed.
Timing of Corticosteroid Administration. As discussed earlier,
most CS therapy is dosed in the morning but there may be reasons
for varied dosing in varied diseases and clinical scenarios. At least
in patients with rheumatoid arthritis, the cytokines (especially
IL-6) contributing to morning stiffness are released in the middle
of traditional sleep timing; thus, the AM CS dose may be too late
to suppress the IL-6 surge. In contrast, night-time dosing of CS
152 PA RT I V Systemic Immunomodulatory Drugs

TABLE 117
13.12 Drug Interactions—Systemic Corticosteroids

Drug Category Drug Examples Comments

Relatively High-Risk Drug
Antidiabetic therapies
Anti-inflammatory
Anticoagulants
Immunosuppressants
Diuretics—potassium losing
Inotropic agents
Vaccines
Macrolide, azalide antibacterials
Antifungals (azoles, triazoles)
Hormonal contraceptives
Interactionsa
Insulin, OHGA, many others ↑ Insulin resistance with resultant potential for severe hyperglycemia
Aspirin, NSAID In combination may ↑ PUD risk and subsequent GI hemorrhage
Warfarin CS may potentiate anticoagulant effects of warfarin
Wide variety—relatively uncommon to Biologics, JAK inhibitors, traditional (azathioprine, cyclosporine,
have these SAE in dermatology mycophenolates, etc.), chemotherapy with risk of severe infec-
tions and/or myelosuppression
Thiazides, loop diuretics Potassium depleting effects of CS may ↑ risk of hypokalemia and
resultant toxicities
Digoxin same
Live attenuated (Zostavax, etc.) Small risk of prednisone dose <20 mg, <2 weeks; still ideally vac-
cinate 2 weeks before start CS
Erythromycin >> clarithromycin > CYP3A4 inhibitors can ↑ CS drug levels and resultant toxicity—DM,
azithromycin high blood pressure, ↑ lipids, etc. (likely a more significant risk
with dexamethasone, methylprednisolone)
Ketoconazole >> itraconazole > fluco- same
nazole (only ≥300 mg daily)
Various CYP3A4 substrates; can ↑ CS half-life, ↓ clearance with resultant ↑
CS levels

Lower-Risk Drug Interactions

Rifamycin antibacterials Rifampin, rifabutin, rifapentine CYP3A4 induction with resultant ↓ CS drug levels and loss efficacy;
this effect takes 1–2 weeks; especially with dexamethasone,
methylprednisolone
Aromatic anticonvulsants Phenytoin, carbamazepine, oxcarbaze- same
pine, phenobarbital
Antifungals Griseofulvin same
Antituberculous Isoniazid Unknown mechanism ↓ CS drug levels
Vitamin D3 Calcitriol May ↓ calcitriol therapeutic effect; unknown mechanism

Bile acid sequestrants Cholestyramine May ↓ CS absorption with loss of efficacy; give CS 2 hours before or
6 hours after cholestyramine

CS, Corticosteroid; CYP, cytochrome P-450; DM, diabetes mellitus; GI, gastrointestinal; HBP, high blood pressure; JAK, janus kinase; NSAID, nonsteroidal anti-inflammatory drug; OHGA, oral hypoglycemic
agent; PUD, peptic ulcer disease; SAE, serious adverse event.
aOverall highest-risk drug interactions indicated in bold italics.

Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/); Hansten PD, Horn JR. The Top 100 Drug Interactions:
A Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications, 2019. (http://www.hanstenandhorn.com/).

tends to produce greater HPA-axis suppression. One study evalu-
ated a 4-hour delayed-release version of prednisone that, when
taken at 10:00 PM and released at 2:00 AM, can better suppress
the IL-6 (and other cytokines) that produce morning stiffness. It
is possible that similar dermatologic applications of this delayed-
release prednisone are forthcoming.
Corticosteroid Dosing Principles for Children. Chronic sys-
temic CS therapy for dermatologic conditions are uncommonly
required in pediatric patients.113,114 Conditions such as severe
Rhus dermatitis will occasionally require a 2 to 3-week burst of
CS. Typically, 1 mg/kg daily is initially given; the dose is halved
every 4 to 7 days. This approach has no significant sustained effect
on growth and is safe for the pediatric patient who has no signifi-
cant relative contraindications.
Corticosteroid Formulation Choice. Prednisone is generally
the systemic CS of choice for most dermatoses. Prednisone is
inexpensive and comes in multiple dosage options, which allows
easy titration of the dose to obtain maximal therapeutic efficacy
and safety. The prednisone dosage ranges are reasonably well stan-
dardized for most conditions treated. In addition, the prednisone
duration of action is optimal for allowing daily or alternate-day
therapy. In Europe, prednisolone is commonly used instead of
prednisone. Prednisolone (1) requires no metabolic conversion to
be active, (2) has a quicker onset of action, and (3) has a CBG
affinity greater than that of prednisone. Drawbacks to routine
prednisolone use include its greater cost and smaller number of
dosage options (only 5-mg tablets, plus liquid formulations of 5
mg/5 mL and 15 mg/5 mL available).

• BOX 13.7 Corticosteroid Monitoring Guidelines13,93,102,117,120–122
Baseline (When Anticipating Long-term Corticosteroid Therapy)
History
• Obtain vaccination history [hemophilus influenza B, hepatitis A, hepatitis
B, human papillomavirus, influenza, neisseria meningitides, rubella (for
women of childbearing age), streptococcus pneumoniae, tetanus toxoid,
varicella zoster]
Examination
• Blood pressure, weight
• Height and weight plotted on a growth curve (in children)
• Ophthalmoscopic examination for cataracts
Laboratory
• Tuberculosis screening—interferon-γ-releasing assay > tuberculin skin
test, chest x-ray
• Strongly consider screening for hepatitis B, hepatitis C, human
immunodeficiency virus
• Consider screening for Strongyloides in endemic areas (rural Appalachia,
immigrants)
• Fasting glucose or hemoglobin A1c and triglycerides; potassium level
• Baseline bone densitometry
Additional Measures
• Initiate calcium 1200 mg and vitamin D 800 IU daily; consider
bisphosphonate if appropriate (alendronate or risedronate
recommended)
• Initiate proton pump inhibitor if indicated for gastrointestinal prophylaxis
• Discuss vaccination with primary care in accordance with standard
scheduling
TABLE Corticosteroid Adverse Effects for Which Home
13.13 Monitoring by the Patient is Possible
Adverse Effect Home Monitoring Measure
Hyperglycemia Home glucose monitoring devices
Hypertension Home blood pressure cuffs/electronic devices
Fluid overload Weighing self on bathroom scale
Weight gain Weighing self on bathroom scale
Overall, the MC effect and duration of action are much more
important factors in the choice of CS therapy than is the anti-
inflammatory potency of the product. Various preparations have
equivalent anti-inflammatory efficacy at therapeutically equivalent
doses. As per Table 13.1, (1) cortisol and cortisone have the great-
est MC activity, (2) dexamethasone, betamethasone, and meth-
ylprednisolone have the least MC activity, and (3) prednisolone,
prednisone, and triamcinolone have intermediate MC activity.
Prednisone and prednisolone share a reasonable profile of MC effect
and duration of action compared with other short-acting alterna-
tives. Lower-potency short-acting CS such as hydrocortisone may
not allow for steady day-long control of the disease activity. The
MC effect of hydrocortisone is excessive, should the potential for
sodium and fluid retention be deleterious to a specific patient.
Hypertension from CS appears to be largely independent of
their natriuretic effect, and is probably more related to vasocon-
striction and increase myocardial contractility. The long-acting CS
betamethasone and dexamethasone produce a much greater risk
of HPA-axis suppression than intermediate-acting CS (prednisone,
CHAPTER 13 Systemic Corticosteroids 153
• Consider pneumocystis pneumonia prophylaxis if appropriate
Follow-up (With Long-term CS Therapy above Physiologic Dose
Levels)
Examination
At 1 month, then at least every 2–3 months:
• Blood pressure, weight
• Height and weight plotted on a growth curve (in children)
• Thorough history each visit for adverse effectsa
At least every 6 months initially; at least every 12 months long term:
• Ophthalmologic examination for cataracts and glaucoma
Laboratory
At 1 month, then at least every 3–4 months while on pharmacologic dose CS:
• Potassium levels
• Glucose levels (fasting)
• Triglycerides (fasting)
Near time of cessation of long-term pharmacologic dose CS therapy (optional):
• AM cortisol level (or another suitable test of adrenal function or the
entire HPA axis)
Pulse Intravenous Methylprednisolone Therapy
• Cardiac monitoring (see text discussion)
• Daily electrolyte and glucose levels
More frequent surveillance is needed if laboratory values are abnormal or with high-risk patients.
• BOX 13.8 Important Principles to Maximize the
Safety of Systemic Corticosteroids in
General (See Also Chapter 2)
First and foremost, prescribe systemic corticosteroid (CS) only for
appropriate, well-documented indications
Thoroughly understand (and use all possible measures to avoid) the
most serious potential CS complications.
Stress thorough patient education reinforced by a patient handout,
striving to form a true therapeutic partnership.
Match the aggression of CS therapy with risk of the disease being
treated
Find the lowest possible effective CS dose as soon as possible.
Use a nonperfectionistic mindset for the completeness of disease control.
Use attack (quickly control the disease process), then reasonably quickly
retreat (taper CS) philosophy.
Seek to attain physiologic or alternate-day doses within 1–2 months;
if this is not possible (or unlikely to be possible) use ‘CS-sparing’
therapy.
‘CS-sparing’ therapy in a broad sense includes any topical or systemic
adjunctive therapy which may allow a reduced oral CS dose.
Proactively deal with precipitators for the disease being treated.
In the presence of a relative contraindication for CS therapy, medical
management of this ‘contraindication’ may allow careful CS therapy.
Laboratory monitoring particularly for metabolic changes —potassium,
glucose, triglycerides (likewise follow the blood pressure closely).
In general, the proactive, careful clinician will:
Anticipate (risk factors and relative contraindications)
Prevent (be proactive regarding measures to prevent adverse effects)
Diagnose early (monitor labs, home monitoring, patient awareness)
Manage (should a significant adverse effect occur) potential adverse
effects from CS therapy.
154 PA RT I V Systemic Immunomodulatory Drugs
prednisolone, methylprednisolone). Therefore, if the patient has
high blood pressure (and/or perhaps congestive heart failure),
methylprednisolone (orally) provides the best ‘compromise’ of
intermediate half-life (24–36 hours) and low MC effect.
Tapering Principles. Tapering based on disease activity is per-
formed to avoid undesirable flare-ups of a previously controlled der-
matologic condition (Q13.11, Box 13.9, Table 13.14). Excessively
rapid tapering will occasionally allow a marked rebound of disease
activity, such as that seen at times with brief (<10–14 days) courses of
CS therapy for severe poison ivy/oak (rhus dermatitis). Identification
at the onset of key historical, examination, and laboratory parameters
of disease activity is important to guide tapering of therapy.
At pharmacologic doses it is important to periodically attempt
CS tapering to determine the minimal effective dose that a given
patient requires. A rough guideline for tapering intermediate- to
chronic duration CS therapy (>1 month) would be to reduce the
dose by 20% to 30% every 1 to 2 weeks as disease activity allows.
• BOX 13.9 Long-Term Corticosteroid Taper for
Pemphigus Vulgaris
Prednisone >40 Mg/Day
Taper by 10 mg/week to 40 mg daily
Remain on 40 mg/day for 1 week
Prednisone 40 Mg/Day
Taper by 5 mg/week to 20 mg daily
Remain on 20 mg/day for 1 week
Prednisone 20 Mg/Day
Taper by 2.5 mg/week to 5 mg daily
Remain on 5 mg/day for 1 week
Prednisone 5 Mg/Day
Taper by 1 mg/week until off prednisone
Taper slowly to avoid both disease flare and adrenal insufficiency. This taper may be used for
other dermatoses; clinicians must individualize taper based on disease activity and underlying
comorbidities. More rapid tapering used for less serious dermatoses.
TABLE
13.14 General Principles for Successful Conversion to Alternate-Day Corticosteroid Therapy
Prerequisites Before Conversion to Alternate-Day Therapy
Complete or nearly complete disease control has been attained
Conversion to alternate-day therapy is most likely to succeed when prednisone dose is down to 20–30 mg daily (or less)
Conversion only from daily AM doses (not from divided doses)
Intermediate-duration CS such prednisone essential for alternate-day therapy to succeed
Options for conversion to alternate-day therapya
(1) Double the prior daily dose for the on day, and drop dose for the off day (if mild flare occurs
or for more serious conditions, consider 2.5 times prior daily dose for on day dose)
(2) Gradually increase dose for on day, while decreasing by a similar amount for off day
(3) Keep a constant dose for on day, while gradually decreasing dose for the off day
aOnly options (1) and (2) keep the 2-day total CS dose at least at prior levels before initiating conversion to alternate-day therapy; in general this constant cumulative dose decreases the likelihood of a disease
bForoptions (2) and (3) above, the clinician may continue each dosing level for two or more cycles, depending upon the severity of the disease treated.
CS, Corticosteroid.
More serious conditions, such as pemphigus vulgaris, commonly
require more gradual tapering at intervals of 3 to 4 weeks or more.
An example regimen for long-term CS tapering for pemphigus
vulgaris is outlined in Box 13.9.
The prednisone dose should be increased to the last effective
dose level if a significant disease flare occurs during the tapering
process. When the daily dose exceeds physiologic levels for more
than 1 month, clinicians should always consider attempting alter-
nate-day therapy, discussed as follows.
Nearing the end of long-term high-dose CS therapy, basal HPA
function can be determined through a morning cortisol level. A
cortisol value greater than 10 mg/dL ensures adequate basal HPA
function, although stress doses of CS may still be appropriate as
previously discussed. Most clinical scenarios in dermatology do
not require this morning cortisol testing.
Alternate-day Corticosteroid Therapy. The conceptual basis for
alternate-day therapy is that the anti-inflammatory benefits of CS
therapy persist longer than the duration of HPA-axis suppression when
intermediate-duration CS therapy, such as prednisone, is used.4,115,116
During the ‘off day,’ cell-mediated immunity, white blood cells subset
levels, and potassium excretion all are essentially normalized.
Alternate-day CS therapy should be used to maintain disease
activity suppression once adequate disease control has been obtained
with daily CS therapy. Patients should be aware that complete sup-
pression of disease activity on the ‘off day’ may not be possible.
However, either small prednisone doses or other non-CS therapeu-
tic measures can be used for minor symptoms during the off day.
Q13.11 Various options for conversion from daily to alter-
nate-day CS therapy are listed in Table 13.14. Q13.12 The risk of
cataracts, osteoporosis, and possibly osteonecrosis are not reduced
by alternate-day CS therapy of comparable doses. The HPA-axis
recovery advantages of alternate-day therapy no longer exist once
the dose reaches physiologic levels (10–15 mg of prednisone on
alternate days). If tapering is proceeding quickly, it is reasonable
to finish the tapering schedule with alternate-day doses. Other-
wise, consider converting back to daily prednisone therapy at 5
mg daily (or less) and proceeding slowly with subsequent tapering.
Some authors suggest conversion to the shorter-acting hydrocorti-
sone at this point with unusually long courses of CS.
Examples in mg by daya
(1) 20-20-40-0-40-0
(serious dermatoses consider 20-20-50-0)
(2) 20-20-25-15-30-10-35-5-40-0b
(3) 20-20-20-15-20-10-20-5-20-0b
flare.
 CHAPTER 13 Systemic Corticosteroids 155

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