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CHaPTEr 86 Glucocorticoids 1169

TABLE 86.2 Important Effects of Proinflammatory cytokines, such as interleukin-1β (IL-1β)
Glucocorticoids (GCs) on Primary and and tumor necrosis factor-α (TNF-α), stimulate 11βHSD1 and
Secondary Immune Cells downregulate 11βHSD2 expression. Hence, specific proinflamma-
tory cytokines can modulate local intracellular GC metabolism,
Monocytes/Macrophages which may affect their own proinflammatory effects. More
↓ Number of circulating cells (↓ myelopoiesis, ↓ release) recently, substantial GC metabolism has been shown in joints,
↓ Expression of major histocompatibility complex (MHC) class II since TNF-α and IL-1β induce 11βHSD1 activity in primary
molecules and Fc receptors
↓ Synthesis of proinflammatory cytokines (e.g., interleukin [IL]-2, IL-6, cultures of synovial fibroblasts isolated from synovial tissue biopsy
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tumor necrosis factor [TNF]-α) and prostaglandins specimens from patients with RA.
In a rodent model of immune-mediated arthritis, targeted
T Cells disruption of GC signaling in osteoblasts attenuates joint inflam-
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↓ Number of circulating cells (redistribution effects) mation and cartilage destruction. These results suggest that
↓ Production and action of IL-2 (most important) under the control of endogenous GCs, osteoblasts modulate
immune-mediated inflammatory responses and, as a consequence,
Granulocytes inflammation-induced cartilage damage and bone integrity. These
↓ Number of eosinophil and basophil granulocytes findings are supported by evidence suggesting that the effects
↑ Number of circulating neutrophils
of GCs follow a dose–response curve, with permissive or even
Endothelial Cells stimulatory effects at physiological concentrations and suppressive
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↓ Vessel permeability effects at pharmacological concentrations.
↓ Expression of adhesion molecules
↓ Production of IL-1 and prostaglandins THERAPEUTIC USE

Fibroblasts A wide range of GC molecules are available for clinical use: The
↓ Proliferation common basic structure has been modified to improve their
↓ Production of fibronectin and prostaglandins usefulness in various clinical applications (Fig. 86.4). Despite
their widespread use, the designation of GC treatment regimens
(From Buttgereit F, Saag K, Cutolo M, et al. The molecular basis for the
effectiveness, toxicity, and resistance to glucocorticoids: focus on the treatment of is often imprecise. Recommendations for a standardized nomen-
rheumatoid arthritis. Scand J Rheumatol 2005; 34: 14–21, with permission.) clature for GC therapy are summarized below. 14
Terminology
Although the term steroid is widely used to describe this class of
The Role of Endogenous Glucocorticoids in drugs, it is too broad, as it simply describes chemical compounds
characterized by a common multiple-ring structure (including
Inflammatory Arthritis cholesterol, vitamin D, and sex hormones). Similarly, the terms
Exogenous (therapeutic) and endogenous (physiological) GCs corticosteroid or corticoid are not sufficiently precise, as the adrenal
differ in several respects. The most important differences are in cortex synthesizes not only GCs but also mineralocorticoids
their relative mineralocorticoid and GC (antiinflammatory) and androgens. For these reasons, the terms glucocorticoid or
activities. Exogenous and endogenous GCs also differ in their glucocorticosteroid are preferred; however, glucocorticoid is the
pharmacological characteristics, such as plasma kinetics, metabo- more widely used term.
lism, biological half-life, lipophilicity, drug–receptor interactions, When describing the use of GCs, it is necessary to define the
and nongenomic potencies. 19 drug, the dosage, the route of administration, and the timing,
The actions of exogenous GCs as described above are well frequency, and duration of treatment.
established. In contrast, we know relatively little about the role Different GC drugs have different potencies, and they differ
of endogenous GCs in arthritis. Although GC actions on target in their ability to produce the distinct therapeutic effects discussed
tissues are thought to be determined by GC plasma concentrations above. Drug potencies are usually described by the equivalent
and the tissue-specific density of GCRs, it seems that endogenous dosages (relative potencies) to produce classic genomic effects
GCs are subject to extensive prereceptor metabolism. Within target (Table 86.3). These values have been used for decades, although
cells or tissues, GC action depends not only on plasma hormone the experimental and clinical evidence for their precise relative
levels, receptor expression, and receptor-effector coupling but potency is weak. In practice, relative potencies are useful as a
also on local GC metabolism. Specifically, 11β-hydroxysteroid general therapeutic guideline in daily clinical practice, as long
dehydrogenases appear to govern access of GCs to their cognate as they are not used dogmatically. It has, therefore, been suggested
receptors by changing the balance between active and inactive that we should continue to use relative potencies until more
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GCs within the cell (reviewed in ). Thus the predominant exact data are available and that doses of different GCs should
reductase activity of 11β-hydroxysteroid dehydrogenase type be expressed in terms of “prednisone equivalent” (i.e., doses of
1 (11βHSD1) catalyzes the formation of bioactive cortisol different GCs are expressed as equivalent to milligrams of
from inactive cortisone (in humans) and corticosterone from prednisone [or prednisolone, as the potency of prednisone is
11-dehydrocorticosterone (in rodents). This nicotinamide adenine equal to that of prednisolone]).
dinucleotide phosphate (NADPH)–dependent enzyme is present However, data indicate that the concept of equivalent dosages
in many tissues and usually increases the intracellular availability is only valid for doses less than 100 mg prednisone equivalent
of active GCs. In contrast, 11βHSD2 only possesses dehydrogenase because nongenomic effects come into play at higher doses. The
activity: It inactivates active GCs and therefore decreases the reason this is important is that the relative potencies of different
intracellular concentration of bioactive GCs. GCs to produce these nongenomic effects are completely different