Page 1209 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 86 Glucocorticoids 1173

GCs and cardiovascular disease in RA, even though atherosclerotic
vascular disease is known to be accelerated in patients with Other Adverse Effects
Cushing syndrome. Systemic GC use during pregnancy may also Adverse effects on the HPA axis and on glucose metabolism are
have epigenetic effects leading to adult hypertension in the next reviewed elsewhere, together with neuropsychiatric and oph-
generation. 29 thalmological adverse effects. 30,32,33
Dermatological Adverse Effects IMPORTANCE OF TIMING OF
Skin thinning and ecchymoses are common adverse events with GLUCOCORTICOID ADMINISTRATION
GCs, even at low doses. Cutaneous atrophy results from the
catabolic effects of GCs on keratinocytes and fibroblasts. Purpura In patients with RA, major symptoms, such as pain, inflammation,
and easy bruising in GC-treated patients probably result from and stiffness, vary during the course of the day, usually with
decreased vascular structural integrity. A Cushingoid appearance the highest severity in the morning hours. These symptoms are
is very troubling to patients but is uncommon at doses below preceded by elevated levels of proinflammatory cytokines. On the
the physiological range. One study reported facial fullness (“moon basis of these considerations, it has been proposed that altering the
facies”) in 13% of patients receiving 4–12 mg triamcinolone for timing of GC administration may help optimize RA therapy. 19,34
up to 60 days. These adverse effects are observed in over 5% of
patients exposed to ≥5 mg prednisone equivalent for ≥1 year. The NEW GLUCOCORTICOID RECEPTOR LIGANDS ON
incidence of iatrogenic Cushing syndrome is dose dependent THE HORIZON
30
and generally becomes evident after >1 month of GC therapy.
Alternate-day therapy may reduce the incidence, although there The various mechanisms of GC action provide interesting
are only limited data supporting this concept. GC-induced acne, opportunities for developing optimized GCs and GCR ligands.
hirsutism, and striae are other undesirable dermatological effects
that occur even with lower doses. Selective Glucocorticoid Receptor Agonists
The genomic component mechanisms of transactivation and
Gastrointestinal Adverse Effects transrepression offer the opportunity to develop GCR ligands
GCs are considerably less toxic to the upper gastrointestinal (GI) that predominantly cause transrepression rather than trans-
tract compared with NSAIDs. If GCs independently increase the activation. This concept is based on the proposition that the
risk of GI events (e.g., gastritis, ulceration, bleeding), the effect antiinflammatory properties of GCs mostly result from repression
is slight, with estimated relative risks varying from 1.1 (not of AP-1–stimulated and NF-κB–stimulated synthesis of inflam-
significant) to 1.5 (marginally significant). There have also been matory mediators, whereas their adverse effects are associated
anecdotal reports of intestinal rupture, diverticular perforation, with transactivation of genes involved in metabolic processes.
and pancreatitis attributed to low-dose GC therapy. GCs are Investigators have, therefore, sought novel GCR ligands with high
frequently used concurrently with NSAIDs in RA, and meta- transrepression activity but low effect on transactivation. One
analyses have confirmed that the combination of the two drugs such compound, A276575, exhibits a high affinity for the GCR
synergistically increases the risk of adverse GI events. In a large- and potently represses IL-1α–induced IL-6 production, similar
scale study based on the UK General Practice Research Database, to dexamethasone. However, unlike dexamethasone, A276575
the risk of upper GI complications was 1.8 (95% confidence induces little aromatase activity. Other novel nonsteroidal GCR
interval [CI] 1.3–2.4) times higher in GC users than in nonusers. ligands that possess high repression activities against inflammatory
The risk tended to be greater with higher GC doses, but the dose mediator production but have lower transactivation activities
gradient was not statistically significant. The risk was >12 times than traditional GC are being developed. Substances that cause
higher in those taking both GCs and NSAIDs than in those not a receptor conformation preferring a GCR–protein interaction
using either. No studies have yet looked at the GI effects of as opposed to a GCR/DNA binding–dependent mechanism
combining GCs with cyclooxygenase 2 (COX-2)–selective NSAIDs. are called selective glucocorticoid receptor agonists (SEGRA) or
Preventive strategies for the adverse effects of GC on the GI tract “dissociated glucocorticoids.” The SEGRA concept has, however,
have been reviewed by Caplan et al. 30 been challenged by studies on a mouse knock-in strain with
a dimerization-deficient GCR, which demonstrated that some
Infectious Diseases inflammatory processes can be suppressed by GCs and others
35
Medium- to high-dose GC therapy may increase the risk of cannot. Also, these mice exhibited the classic adverse effects
serious infections leading to hospitalization or surgery, particularly of GCs, such as GC-induced osteoporosis. Thus depending on
when administered for prolonged periods. However, there is no the process being treated, SEGRA could be therapeutically more
evidence that infection rates are increased in patients on doses effective or less effective; moreover, not all adverse effects of GC
of prednisone below 10 mg/day or cumulative doses below therapy may be reduced. 35,36 As of now, whether SEGRA will
700 mg. In those taking higher doses, the risk of infection appears become clinically relevant in practice remains uncertain.
to be lessened with alternate-day therapy.
In GC-treated patients, physicians should be aware of the Nitrosteroids
risk of infections with typical and atypical organisms, recognizing Nitrosteroids are another new class of GC drugs that have been
that GCs may blunt classic clinical features and delay diagnosis. tested in RA and inflammatory bowel disease (IBD). In addition
However, it is difficult to separate the independent effects of GC to their enhanced GC properties, nitrosteroids release low levels
use from those of other commonly used antirheumatic agents, of NO and have fewer undesirable effects. The prototype of these
31
such as methotrexate and anti-TNF-α agents. At present, the new steroids, 21-NO-prednisolone (NCX-1015), is much more
independent role of GCs in facilitating herpes zoster virus (HZV) potent than prednisolone in models of acute and chronic inflam-
infection in patients with RA remains uncertain. mation, including experimental arthritis induced by collagen II.