Systemic anti-infl ammatory agents

Systemic corticosteroid therapy

Corticosteroids were first introduced into dermatology by Marion
Sulzberger [1]. Most of their effects are mediated by the intracellular
glucocorticoid receptor via activation or repression of gene
expression [2,3]. Activation requires DNA binding of the receptor,
while repression is mediated by protein–protein interactions with
other transcription factors. The immunosuppressive and antiinfl
ammatory effects are exerted mainly by an interaction of the
glucocorticoid receptor with the activating protein 1 (AP-1)
and nuclear factor B (NF-B) families of transcription factors
without DNA binding. Cytokines such as tumour necrosis factor-
(TNF-) and interleukin 1 (IL-1) activate the hypothalamus–
pituitary–adrenal (HPA) axis; glucocorticoids inhibit IL-1 and
TNF-, forming a cytokine–HPA axis feedback circuit. In addition,
glucocorticoids induce apoptosis of infl ammatory cells of the
haematopoietic system, such as monocytes, macrophages and T
lymphocytes, while protecting resident tissue cells [4]. Corticosteroids,
by evoking formation of a cell-membrane protein termed
lipocortin, also inhibit phospholipase A2 (PLA2), a membrane
enzyme that generates a variety of pro-infl ammatory lipids from
membrane phospholipids, including the prostaglandins, the leukotrienes
and platelet-activating factor [5]. Other proposed mechanisms
of corticosteroids include a cytostatic action, a ‘stabilizing’
action on lysosomal membranes and suppression of cytokine
expression. Glucocorticoid effects on bone result from inhibition
of bone formation because of a decrease in the number and function
of osteoblasts, and increased bone resorption resulting from
osteoclastogenesis (with increased expression of RANK ligand
and decreased expression of its decoy receptor, osteoprotegerin),
as well as stimulated expression of collagenase 3 [6]. Corticosteroids
inhibit dendritic cell function [7].
Indications
Systemic corticosteroid treatment, rather than topical corticosteroid
therapy, is indicated in special circumstances only. These
include the following:
1 Acute self-limited steroid-sensitive disorders (e.g. acute contact
allergic dermatitis), where the offending allergen is evident. In
these circumstances a 1-week course of oral prednisone in
reducing dosage may be suffi cient.
2 Acute anaphylactic reactions (e.g. following a bee or wasp sting
or a drug to which the patient is sensitized). Hydrocortisone
should be given intravenously in a dose of 100 mg, after prior
administration of epinephrine (adrenaline) 0.5 mg intramuscularly,
and chlorphenamine (chlorpheniramine) 4 mg intramuscularly
(adult doses).
3 Acute autoimmune connective tissue diseases and generalized
immunological vascular disorders (e.g. systemic lupus erythematosus,
dermatomyositis, polyarteritis nodosa, giant cell arteritis,
Wegener’s granulomatosis).
4 Chronic disabling immunological bullous diseases (e.g. pemphigus
vulgaris, pemphigoid).
5 Acute generalized exfoliative dermatitis (e.g. resulting from a
severe drug reaction).
6 A number of miscellaneous disorders including severe lichen
planus, pyoderma gangrenosum and sarcoidosis, in which there
is evidence of cardiac, renal, ocular or extensive pulmonary or
cutaneous involvement.
7 Although systemic steroids are often used, the value of such
treatment is unproven in erythema multiforme, Stevens–Johnson
syndrome, toxic epidermal necrolysis, chronic urticaria and
cutaneous T-cell lymphoma.
Pharmacological considerations
Corticosteroids are anti-infl ammatory, immunosuppressive, antiproliferative
and vasoconstrictive.
Prednisone and prednisolone
Like cortisone and hydrocortisone, prednisone and prednisolone
differ chemically only in the presence of a hydroxy group instead
of a keto group at C11. The biological properties are similar, but
prednisone has to be metabolically transformed in the liver to the
11-hydroxy derivative to acquire biological potency, and hence
prednisone should not be given to patients with liver disease. Both
drugs possess four times the glucocorticoid potency and relatively
less mineralocorticoid (salt-retaining) activity than hydrocortisone
and cortisone.
Route of administration
Intramuscular
The intramuscular route, especially for triamcinolone, is popular
in the USA for systemic steroid administration for short-term (less
than 4 weeks) treatment. Triamcinolone does not differ signifi -
cantly from prednisolone in its actions on a short-term basis,
although in the long term it possesses greater mineralocorticoid
activity. In the longer term, intramuscular steroids, especially in
depot formulation, can cause marked HPA suppression and severe
local atrophic changes, although the latter partially remit after a
year or more. In the event of untoward steroid-induced complications,
the drugs cannot be withdrawn promptly.
Intravenous
The intravenous route is useful in emergency treatment of acute
anaphylaxis and in the pre- and postoperative cover of patients who have previously been receiving
systemic steroid treatment for 4 weeks or more. A suitable regimen is 25 mg hydrocortisone preoperatively
at the time of induction of anaesthesia, 100 mg

during the operation and 100 mg on the fi rst postoperative day—

all doses being intravenous.
Thereafter the patient can be maintained on oral therapy as
required. In fact, hypotensive crises attributable to adrenal insuffi
ciency are extremely rare in patients withdrawn from glucocorticoid
therapy and subsequently undergoing surgery without
supplemental corticosteroid cover.
Pulsed steroid therapy
This is usually administered as doses of 1 g of methylprednisolone
given intravenously over several hours using an intravenous line.
The dose can be repeated daily for up to 5 days. It may be indicated
in patients with severe bullous dermatoses, especially pemphigus
vulgaris. It is a potentially hazardous procedure, and
thromboembolism, cardiac arrest and steroid psychosis are occasional
complications [8].
Oral steroids
Oral steroids may be taken in a single daily dose or using an
alternate-day regimen.
Single daily dose. Short-term systemic steroid therapy is best
given as a single daily dose. Prednisone and prednisolone have
minimal mineralocorticoid activity and have a suffi ciently prolonged
action to ensure the sustained effectiveness of a single
daily dose. The single dose should be given fi rst thing in the
morning. This is because the maximum rate of adrenocortical
cortisol secretion occurs early in the morning and therefore less
pituitary–adrenal suppression occurs at this time, while therapeutic
effi cacy is maintained [9].
Alternate-day dosage. Prolonged therapy may be instituted
using an alternate-day regimen (twice the daily dose on alternate
days with no steroid treatment on the other days) [10]. Conversion
from a daily to an alternate-day regimen should be carried out
gradually rather than abruptly (e.g. by progressive diminution of
the dose on even-numbered days while building up the dose on
odd-numbered days). In order to prevent alternate-day relapses,
it may be necessary to maintain a small dose on the even-numbered
day. Institution of an alternate-day systemic steroid regimen
reduces but does not prevent steroid toxicity. Posterior subcapsular
cataracts and osteoporosis may remain problems [11–13].
Alternate-day systemic steroid therapy is not always as effective
as daily treatment when given in equivalent dosage.
Systemic steroid toxicity
A comprehensive account of the range of unwanted side effects
consequent upon systemic steroid therapy is beyond the scope of
this text, and is addressed in Chapter 75. Betamethasone and
defl azacort may be used in emergencies in patients with adverse
immunoglobulin E (IgE)-mediated allergic reactions to hydrocortisone
and methylprednisolone [14].
The approximate physiological daily cortisol secretion by the
adrenal cortex is 20 mg/day for an average adult (prednisone
equivalent 5 mg/day). Short courses of prednisolone (e.g. up to
30 mg/day for less than 2 weeks), although suppressing pituitary–
adrenal function, do not require tapering because recovery
is rapid. However, for patients with a longer history of oral steroid
treatment, gradual reduction of dosage prior to discontinuation is
important, because abrupt reduction may lead to the ‘steroidwithdrawal’
syndrome, which resembles the clinical features of
adrenocortical insuffi ciency. Random plasma-cortisol determination
may be within normal limits and stimulation tests of pituitary
and adrenal function may also be normal [15].
One of the major problems with prolonged systemic corticosteroid
therapy is osteoporosis. Patients receiving the equivalent of
prednisolone 7.5 mg/day or more for over 3 months should
receive prophylactic therapy to prevent bone resorption, such as
calcium, bisphosphonates (alendronate, etidronate or risedronate),
calcitriol or gonadal steroids (hormone replacement therapy in
women, testosterone in men) [16–21]. Corticosteroid-induced lipodystrophy
may also be a problem [22]. Common mood disturbances
include hypomania and euphoria, and less common ones
are depression, psychosis or delirium. They usually occur within
the fi rst 2 weeks of corticosteroid therapy and seem to be dose
related; the elderly are particularly at risk [23–25].
Tests of pituitary–adrenal function
Baseline plasma-cortisol levels and study of diurnal variation of
plasma cortisol are crude estimates of HPA integrity. The adrenocorticotrophic
hormone (ACTH) stimulation test measures adrenal
but not hypothalamo-pituitary integrity. The metyrapone test is
based upon inhibition of an enzyme involved in synthesis of a
cortisol precursor (2-deoxycortisol) resulting in reduction in cortisol
levels and a consequent increase in ACTH. The cortisol precursors
are measured in the urine and the resultant values give an
indication of HPA integrity. Stress tests including insulin-induced
hypoglycaemia measure the integrity of the whole HPA system,
and are best carried out with the assistance of a specialized unit.
Systemic corticosteroids and pregnancy
There is little concrete evidence that systemic corticosteroids are
harmful in pregnancy. Although the literature contains sporadic
reports of stillbirth, spontaneous abortion and cleft palate associated
with systemic corticosteroids [26], a recent review concluded
that they are not teratogenic. Very little corticosteroid ingested by
a mother enters her breast milk [27]. Children exposed to courses
of antenatal corticosteroids do not differ signifi cantly in physical
or neurocognitive measures from their peers at 2 years of age
[28,29].
Systemic corticosteroids and cataracts
Posterior subcapsular cataracts are a recognized complication of
systemic corticosteroid therapy. Screening by slit-lamp examination
for patients in whom prolonged treatment with systemic corticosteroids
is contemplated may help to obviate medicolegal
consequences [11].
ACTH and tetracosactide
Although these agents are not corticosteroids, they provoke
increased secretion of endogenous adrenal corticoids. There
is little or no evidence to support the use of ACTH or tetracosactide
(tetracosactrin) in place of systemic steroids. Their anti-infl ammatory actions depend entirely upon
increased hydrocortisone
production by the adrenal cortex. They also suffer from
the disadvantage that they stimulate adrenal androgen as well as
hydrocortisone production, and therefore cause more salt and
water retention than prednisolone [30]. Maximum response of
adult adrenals is no more than 100 mg/day cortisol. ACTH and
tetracosactide have to be given by injection and can cause severe
anaphylactic reactions. There is no sound evidence for the often
asserted view that these drugs are associated with less growth
retardation in children than with oral corticosteroids. The only
arguable advantage of ACTH or tetracosactide therapy is a reduced
likelihood of pituitary–adrenal suppression, and this view has
been challenged [30]. Certainly, overall, and dose for dose, manifestations
of steroid toxicity are at least as frequent as in oral corticosteroid
treatment.
References
1 Sulzberger MB, Witten VH. The effect of topically applied compound E in
selected dermatoses. J Invest Dermatol 1952; 19: 101–2.
2 Schaaf MJ, Cidlowski JA. Molecular mechanisms of glucocorticoid action and
resistance. J Steroid Biochem Mol Biol 2002; 83: 37–48.
3 Neeck G, Renkawitz R, Eggert M. Molecular aspects of glucocorticoid hormone
action in rheumatoid arthritis. Cytokines Cell Mol Ther 2002; 7: 61–9.
4 Amsterdam A, Sasson R. The anti-infl ammatory action of glucocorticoids is
mediated by cell type specifi c regulation of apoptosis. Mol Cell Endocrinol 2002;
189: 1–9.
5 Flower RJ. Background and discovery of lipocortins. Agents Actions 1986; 17:
255–62.
6 Canalis E, Delany AM. Mechanisms of glucocorticoid action in bone. Ann N Y
Acad Sci 2002; 966: 73–81.
7 Suda T, Chida K, Matsuda H, Hashizume H et al. High-dose intravenous glucocorticoid
therapy abrogates circulating dendritic cells. J Allergy Clin Immunol
2003; 112: 1237–9.
8 White KP, Driscoll MS, Rothe MJ, Grant-Kels JM. Severe adverse cadiovascular
effects of pulse steroid therapy: is continuous cardiac monitoring necessary?
J Am Acad Dermatol 1994; 30: 768–73.
9 Nugent CA, Ward J, MacDiamid WD et al. Glucocorticoid toxicity: single versus
divided daily doses of prednisolone. J Chron Dis 1965; 18: 323–32.
10 Reichling GH, Kligman AM. Alternate-day corticosteroid therapy. Arch Dermatol
1961; 83: 980–3.
11 Castrow FF. Atopic cataracts versus steroid cataracts. J Am Acad Dermatol 1981;
5: 64–6.
12 MacGregor RR, Sheagren JN, Lipsett MB et al. Alternate-day prednisone therapy:
evaluation of delayed hypersensitivity responses, control of disease and steroid
side-effects. N Engl J Med 1969; 280: 1427–31.
13 Gallant C, Kenny P. Oral glucocorticoids and their complications: a review. J Am
Acad Dermatol 1986; 14: 161–77.
14 Ventura MT, Calogiuri GF, Matino MG et al. Alternative glucocorticoids for use
in cases of adverse reaction to systemic glucocorticoids: a study on 10 patients.
Br J Dermatol 2003; 148: 139–41.
15 Amatruda TT, Hollingsworth DR, D’Esopo G et al. A study of the mechanism
of the steroid withdrawal syndrome: evidence for integrity of the hypothalamic–
pituitary–adrenal system. J Clin Endocrinol 1960; 20: 339–54.
16 Summey BT, Yosipovitch G. Glucocorticoid-induced bone loss in dermatologic
patients: an update. Arch Dermatol 2006; 142: 82–90.
17 Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis:
pathophysiology and therapy. Osteoporos Int 2007; 18: 1319–28.
18 Leonard MB. Glucocorticoid-induced osteoporosis in children: impact of the
underlying disease. Pediatrics 2007; 119 (Suppl. 2): S166–74.
19 Gourlay M, Franceschini N, Sheyn Y. Prevention and treatment strategies for
glucocorticoid-induced osteoporotic fractures. Clin Rheumatol 2007; 26: 44–53.
20 Curtis JR, Saag KG. Prevention and treatment of glucocorticoid-induced osteoporosis.
Curr Osteoporos Rep 2007; 5: 14–21.
21 De Nijs RN. Glucocorticoid-induced osteoporosis: a review on pathophysiology
and treatment options. Minerva Med 2008; 99: 23–43.
22 Fardet L, Cabane J, Lebbé C et al. Incidence and risk factors for corticosteroidinduced
lipodystrophy: a prospective study. J Am Acad Dermatol 2007; 57:
604–9.
23 Brown ES, Khan DA, Nejtek VA. The psychiatric side effects of corticosteroids.
Ann Allergy Asthma Immunol 1999; 83: 495–503.
24 Warrington TP, Bostwick JM. Psychiatric adverse effects of corticosteroids. Mayo
Clin Proc 2006; 81: 361–7.
25 Cerullo MA. Expect psychiatric side effects from corticosteroid use in the elderly.
Geriatrics 2008; 63: 15–8.
26 Reinisch JM, Simon NG, Karow WG et al. Prenatal exposure to prednisolone in
humans and animals retards uterine growth. Science 1978; 202: 436–8.
27 Lockshin MD, Sammaritano LR. Corticosteroids during pregnancy. Scand J Rheumatol
1998; 107 (Suppl.): 136–8.
28 Crowther CA, Doyle LW, Haslam RR et al. Outcomes at 2 years of age after
repeat doses of antenatal corticosteroids. N Engl J Med 2007; 357: 1179–89.
29 Wapner RJ, Sorokin Y, Mele L et al. Long-term outcomes after repeat doses of
antenatal corticosteroids. N Engl J Med 2007; 357: 1190–8.
30 Hirschmann JV. Some principles of systemic glucocorticoid therapy. Clin Exp
Dermatol 1986; 11: 27–33.