N IH
`
`C O N F E R E N CE
`
`Glucocorticoid Therapy for Immune-mediated Diseases:
`Basic and Clinical Correlates
`Moderator: Dimitrios T. Boumpas, MD; Discussants: George P. Chrousos, MD;
`Ronald L. Wilder, MD, PhD; Thomas R. Cupps, MD; and James E. Balow, MD
`
`• Glucocorticoids are pleiotropic hormones that at
`pharmacologic doses prevent or suppress inflamma(cid:173)
`tion and other immunologically mediated processes. At
`the molecular level, glucocorticoids form complexes
`with specific receptors that migrate to the nucleus
`where they interact with selective regulatory sites
`within DNA; this results in positive and negative mod(cid:173)
`ulation of several genes involved in inflammatory and
`immune responses. At the cellular level, glucocorti(cid:173)
`coids inhibit the access of leukocytes to inflammatory
`sites; interfere with the functions of leukocytes, endo(cid:173)
`thelial cells, and fibroblasts; and suppress the produc(cid:173)
`tion and the effects of humoral factors involved in the
`inflammatory response. Clinically, several modes of
`glucocorticoid administration are used, depending on
`the disease process, the organ involved, and the extent
`of involvement. High doses of daily glucocorticoids are
`usually required in patients with severe diseases involv(cid:173)
`ing major organs, whereas alternate-day regimens may
`be used in patients with less aggressive diseases.
`Intravenous glucocorticoids (pulse therapy) are fre(cid:173)
`quently used to initiate therapy in patients with rapidly
`progressive, immunologically mediated diseases. The
`benefits of glucocorticoid therapy can easily be offset
`by severe side effects; even with the greatest care, side
`effects may occur. Moreover, for certain complications
`(for example, infection diathesis, peptic ulcer, osteoporo(cid:173)
`sis, avascular necrosis, and atherosclerosis), other drug
`toxicities and pathogenic factors overlap with glucocor(cid:173)
`ticoid effects. Minimizing the incidence and severity of
`glucocorticoid-related side effects requires carefully de(cid:173)
`creasing the dose; using adjunctive disease-modifying
`immunosuppressive and anti-inflammatory agents; and
`taking general preventive measures.
`
`Ann Intern Med. 1993;119:1198-1208.
`
`Dr. Dimitrios T. Boumpas (Kidney Disease Section,
`National Institute of Diabetes and Digestive and Kidney
`Diseases
`[NIDDK], National
`Institutes of Health
`
`[NIH], Bethesda, Maryland): Since 1949, when Hench
`and colleagues first introduced cortisone for the treat(cid:173)
`ment of rheumatoid arthritis, glucocorticoids have rev(cid:173)
`olutionized the treatment of immunologically mediated
`diseases. Although substantial complications associated
`with glucocorticoids have tempered enthusiasm for their
`use, they have remained the cornerstone of therapy for
`virtually all immunologically mediated diseases. In re(cid:173)
`cent years, an explosion of new information has oc(cid:173)
`curred relevant to both basic and clinical aspects of
`glucocorticoid therapy.
`We describe the molecular mechanisms, sites of ac(cid:173)
`tion, and effects of glucocorticoids on various cells in(cid:173)
`volved in inflammatory and immunologically mediated
`reactions. Treatment principles are also provided with
`examples of specific glucocorticoid regimens in proto(cid:173)
`typical conditions. We also review selective complica(cid:173)
`tions of glucocorticoid therapy and discuss recent infor(cid:173)
`mation about their pathogenesis and management.
`
`Mechanisms of Action
`
`Dr. George P. Chrousos (Chief, Pediatric Endocrinol(cid:173)
`ogy Section, Developmental Endocrinology Branch,
`National Institute of Child Health and Human Develop(cid:173)
`ment, NIH, Bethesda, Maryland): Glucocorticoids exert
`most of their effects through specific, ubiquitously dis(cid:173)
`tributed intracellular receptors (1). The classic model of
`glucocorticoid action was described more than two de(cid:173)
`cades ago and is briefly updated here (Figure 1, panel
`A). Glucocorticoids circulate in blood, is either in the
`free form or in association with cortisol-binding globu(cid:173)
`lin. The free form of the steroid can readily diffuse
`through the plasma membrane and can bind with high
`affinity to cytoplasmic glucocorticoid receptors (the role
`of receptors primarily residing in the nucleus is contro(cid:173)
`versial). The formation of the ligand-receptor complex
`is followed by its "activation" (that is, translocation
`into the nucleus and binding to what are called "accep(cid:173)
`tor sites"). The bound complex modulates transcription
`of specific genes that encode proteins responsible for
`the action of glucocorticoids.
`
`An edited summary of a Clinical Staff Conference held 30 December
`1992 at the Amphitheater, Building 10, Bethesda, Maryland. The con(cid:173)
`ference was sponsored by the National Institute of Diabetes and Diges(cid:173)
`tive and Kidney Diseases, National Institutes of Health, U.S. Depart(cid:173)
`ment of Health and Human Services.
`Authors who wish to cite a section on the conference and specifically
`indicate its author may use this example for the form of reference:
`Chrousos GP. Mechanisms of action, pp 1198-1200. In: Boumpas
`DT, moderator. Glucocorticoid therapy for immune mediated dis(cid:173)
`eases: basic and clinical correlates. Ann Intern Med. 1993;119:1198-
`1208.
`
`Glucocorticoid Receptors
`
`In 1985, the complementary DNA of the human glu(cid:173)
`cocorticoid receptor was cloned (2); it contains three
`main functional domains (Figure 1, panel B): first, the
`DNA-binding domain in the center of the molecule that
`recognizes specific sequences of the DNA called hor(cid:173)
`mone-responsive elements; second, the ligand-binding
`domain in the carboxyl terminal region that interacts
`
`1198 15 December 1993 • Annals of Internal Medicine • Volume 119 •
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`JANSSEN EXHIBIT 2021
`Mylan v. Janssen IPR2016-01332
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`Figure 1. Mechanisms of glucocorticoid action. Panel A. Steroid hormone (S) circulates as a free molecule or as a complex with
`plasma-binding protein. After the steroid enters the cell, it binds to receptors (R) that reside in the cytosol complexed to heat-shock
`protein (HSP) and immunophilin (IP). Binding of the ligand to the complex causes dissociation of HSP and IP. The receptor-ligand
`translocates into the nucleus where it binds at or near the 5'-flanking DNA sequences of certain genes (glucocorticoid-responsive
`elements [GRE]). Receptor binding to the regulatory sequences of the responsive genes increases or decreases their expression. In
`the first instance (ON), glucocorticoids increase the transcription or stability or both of messenger RNA, which is translated on
`ribosomes to the designated protein. In the second instance (OFF), glucocorticoids repress (cross-hatched arrows) certain genes
`at the transcriptional level by interacting with and preventing the binding of nuclear factors required for activation of the gene (for
`example, activator protein (AP)-l nuclear factor). In other instances, glucocorticoids exert their effects post-transcriptionally by
`either increasing the degradation of messenger RNA or by inhibiting the synthesis or secretion of the protein. Panel B. The three
`main domains (immunogenic, DNA-binding, and ligand-binding) of the glucocorticoid receptor represented in a linear model. At left
`are the indicated domains and amino acid sequences of the receptor (see text for details). HSP 90 = heat-shock protein 90; NLSj
`and NLS2 = nuclear localization sequences 1 and 2; rx and r2 = transactivation domains 1 and 2.
`
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`with the specific steroid; and third, the "immunogenic"
`domain in the amino terminal region.
`The nonactivated glucocorticoid receptor resides in
`the cytosol in the form of a hetero-oligomer with other
`highly conserved proteins (3). This molecular complex
`comprises receptor, heat-shock proteins, and immuno-
`philin (Appendix Table 1) (4). The binding of the recep(cid:173)
`tor to the heat-shock protein 90 facilitates its interaction
`with the ligand (5). When the ligand binds, the receptor
`dissociates from the rest of the hetero-oligomer and
`translocates into the nucleus. Before or after the trans(cid:173)
`location, the receptor forms homodimers through se(cid:173)
`quences present in the DNA and ligand-binding do(cid:173)
`mains (6).
`
`Gene Regulation
`
`After specific interaction with pore-associated pro(cid:173)
`teins, the hormone-receptor complexes enter the nu(cid:173)
`cleus through the nuclear pores (7). The interaction is
`facilitated by two nuclear localization sequences in the
`receptor, both in the ligand-binding domain. Inside the
`nucleus, the hormone-receptor complexes bind to spe(cid:173)
`cific glucocorticoid responsive elements within DNA
`(8). The complexes modulate the transcription rates of
`the corresponding glucocorticoid-responsive genes (9),
`apparently by stabilizing the initiation complex, com(cid:173)
`posed of RNA polymerase II and its ancillary factors A
`through F. The hormone-receptor complex may interact
`directly with factor IIB (10), but it also interacts with
`other nuclear proteins to produce the conditions neces(cid:173)
`sary for effective transcription (11). These proteins may
`be able to relax the DNA away from the nucleosome
`and thus make it easier for the polymerase to exert its
`effects. In addition, glucocorticoid receptors may inter(cid:173)
`act with DNA-binding proteins that are associated with
`different regulatory elements of the DNA (12, 13). At
`least two such proteins have been described: One is the
`glucocorticoid modulatory element-binding protein and
`the other is the CACCC-box-binding protein. Both of
`these transcription factors potentiate the modulatory ef(cid:173)
`fects of glucocorticoids after transcription of specific
`genes.
`Transcription appears to be important in the regula(cid:173)
`tion of genes involved in growth and inflammation. Glu(cid:173)
`cocorticoid response elements can act both positively
`and negatively on transcription, depending on the gene
`on which the complex acts (14, 15). One major way by
`which glucocorticoids exert down-modulatory effects on
`transcription is through noncovalent interaction of the
`activated hormone-receptor complex with the c-Jun/c-
`Fos heterodimer (16-18), which binds to the activator
`protein (AP)-l site of genes of several growth factors
`and cytokines. The glucocorticoid-receptor complex
`prevents the c-Jun/c-Fos heterodimer from stimulating
`the transcription of these genes. Another mechanism by
`which glucocorticoids may suppress gene transcription
`is by an interaction between the hormone-receptor com(cid:173)
`plex and glucocorticoid response elements that are in
`close proximity to responsive elements for other tran(cid:173)
`scription factors (19). Thus, the promoter region of the
`glycoprotein hormone-a subunit, which is stimulated by
`cyclic AMP through the cyclic AMP-responsive ele(cid:173)
`
`ment, contains a glucocorticoid response element in
`close proximity, so that when the receptor dimer binds
`to its own element, it hinders the cyclic AMP-binding
`protein from exerting its stimulatory effect on that gene.
`
`Post-Transcriptional Effects
`
`In addition to modulating transcription, glucocorti(cid:173)
`coids also have effects on later cellular events, including
`RNA translation, protein synthesis, and secretion. They
`can alter the stability of specific messenger RNAs of
`several cytokines and other proteins, thereby altering
`the intracellular steady-state levels of these molecules
`(20, 21). This may occur through modulation of tran(cid:173)
`scription of still unknown proteins that bind RNA and
`alter its translation and degradation rates. Also, gluco(cid:173)
`corticoids influence the secretion rates of specific pro(cid:173)
`teins through mechanisms that have not yet been de(cid:173)
`fined. Finally, the receptor itself has guanylate cyclase
`activity, and glucocorticoids can rapidly alter the elec(cid:173)
`trical potential of some cells (22, 23).
`
`Anti-inflammatory and Immunosuppressive Effects
`
`Dr. Dimitrios T. Boumpas: Although the cause and
`pathogenesis of many immunologically mediated dis(cid:173)
`eases are not completely understood, it is known that
`the localization of leukocytes at sites of inflammation,
`their subsequent activation, and the generation of se(cid:173)
`cretory products contribute to tissue damage, as shown
`in Figures 2 and 3 (24-26). Glucocorticoids inhibit the
`access of leukocytes to inflammatory sites,
`interfere
`with their function and the function of fibroblasts and
`endothelial cells at those sites, and suppress the pro(cid:173)
`duction and the effects of humoral factors. In general,
`leukocyte traffic is more susceptible to alteration by
`glucocorticoids than is cellular function; in turn, cellular
`immunity is more susceptible than humoral immunity to
`these agents.
`Even though the effects of glucocorticoids on the
`different types of inflammatory cells will be discussed
`separately, each cell type is actually involved in com(cid:173)
`plex interactions with other cells. Glucocorticoids affect
`many, if not all, the cells and tissues of the body, thus
`provoking a wide range of changes that involve several
`cell types concurrently.
`
`Effects on Nonlymphoid Inflammatory Cells
`
`Dr. Ronald L. Wilder (Chief, Inflammatory Joint Dis(cid:173)
`eases Section, Arthritis and Rheumatism Branch, Na(cid:173)
`tional Institute of Arthritis and Musculoskeletal and
`Skin Diseases, NIH, Bethesda, Maryland): Glucocorti(cid:173)
`coids are among
`the most potent anti-inflammatory
`agents available
`in clinical medicine. Pharmacologic
`doses of glucocorticoids dramatically inhibit exudation
`of plasma and accumulation of leukocytes at sites of
`inflammation. Several factors influence the magnitude of
`these effects, including the dose and route of adminis(cid:173)
`tration of the glucocorticoids used, as well as the type
`and differentiation state of the target cell population
`(27). Several host variables also modify the anti-inflam(cid:173)
`matory response to glucocorticoids. For example, some
`persons (those with active systemic lupus erythemato-
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`Figure 2. Models of the pathogenesis of inflammation and immune injury. Panel A. The recruitment of leukocytes at sites of
`inflammation, their subsequent activation, and generation of secretory products contribute to tissue damage. Panel B. Circulating
`leukocytes exit the vascular bed in response to chemotactic stimuli (for example, complement 5a [C5a], leukotrienes, interleukin-8
`[IL-8], and transforming growth factor [TGF-fi]) released at sites of inflammation. The interaction of leukocytes with endothelial
`cells lining blood vessel walls represents the first critical step in leukocyte movement into the tissue. This is mediated by cell
`surface glycoproteins called adhesion molecules. The persistent migration and tissue accumulation of leukocytes to local inflam(cid:173)
`matory sites is paramount in initiating or modifying or both many disease processes (24).
`
`sus) appear to have an accelerated rate of glucocorti(cid:173)
`coid catabolism (28). Various levels of target tissue re(cid:173)
`sistance may exist in some patients with systemic lupus
`erythematosus and rheumatoid arthritis (29). These fac(cid:173)
`tors, alone or in combination, may explain the observa(cid:173)
`tion that different patients and diseases have variable
`therapeutic responses to glucocorticoids (30, 31).
`
`Macrophages
`Glucocorticoids antagonize macrophage differentia(cid:173)
`tion and inhibit many of their functions (27). These
`agents 1) depress myelopoiesis and inhibit expression of
`class II major histocompatibility complex antigens in(cid:173)
`duced by interferon-y; 2) block the release of numerous
`cytokines, such as interleukin-1, interleukin-6, and tu(cid:173)
`mor necrosis factor-a; 3) depress production and re(cid:173)
`lease of proinflammatory prostaglandins and
`leuko(cid:173)
`trienes; and 4) depress
`tumoricidal and microbicidal
`activities of activated macrophages.
`
`Neutrophils
`The major effect of glucocorticoids on neutrophils
`appears to be the inhibition of neutrophil adhesion to
`endothelial cells. This effect diminishes trapping of neu(cid:173)
`trophils in the inflamed site and probably is responsible
`for the characteristic neutrophilia. At pharmacologic
`doses, glucocorticoids only modestly impair important
`neutrophil functions, such as lysosomal enzyme release,
`the respiratory burst, and chemotaxis to the inflamed
`
`site. Lower doses do not affect these neutrophil func(cid:173)
`tions (27, 30).
`
`Eosinophils, Basophils, and Mast Cells
`Just as they affect macrophages, glucocorticoids de(cid:173)
`crease circulating eosinophil and basophil counts. They
`also decrease the accumulation of eosinophils and mast
`cells at sites of allergic reactions. Functionally, gluco(cid:173)
`corticoids inhibit IgE-dependent release of histamine
`and leukotriene C4 from basophils, and they also inhibit
`degranulation of mast cells (27).
`
`Endothelial Cells
`These cells form the barrier between the blood and
`the tissues and are critical regulators of the inflamma(cid:173)
`tory cascade. They affect hemostasis, vascular perme(cid:173)
`ability, trapping, and exudation of leukocytes into in(cid:173)
`flammatory sites. Glucocorticoids have profound effects
`on the activation and subsequent function of these cells
`(27) and clearly inhibit vascular permeability. More(cid:173)
`over, they inhibit numerous molecular events associated
`with activation. For example, they inhibit up-regulation
`of the expression of class II major histocompatibility
`complex antigens, as well as endotoxin-induced up-reg(cid:173)
`ulated expression of the adhesion molecules (endothelial
`leukocyte adhesion molecule-1 [ELAM-1] and intercel(cid:173)
`lular cell adhesion molecule-1 [ICAM-1]), which are
`cell surface molecules critical to leukocyte localization
`(24-26, 32) (see Figure 3). Further, glucocorticoids in-
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`activity is mediated by the activation of inhibitors of the
`enzyme itself or by inhibition of enzyme synthesis. The
`primary mediators of the inhibition of enzyme activity
`appear to be members of the "annexin" family of pro(cid:173)
`teins, which includes proteins such as lipocortin-1 (33).
`This topic, however, remains controversial (34-36).
`A second step in prostaglandin synthesis is the for(cid:173)
`mation of prostaglandin H2 from arachidonic acid by
`enzymes called cyclooxygenases. Recent data have
`shown the existence of at least two cyclooxygenase
`(COX) genes, COX-1 and COX-2; the proteins have
`61% amino acid identity. The COX-2 gene and protein,
`but not COX-1, are strongly up-regulated
`in macro(cid:173)
`phages, endothelial cells, and fibroblasts by mediators
`such as endotoxin and interleukin-1, although they are
`inhibited by glucocorticoids. In contrast, COX-1 is con-
`stitutively expressed and relatively unaffected by gluco(cid:173)
`corticoids.
`The role of the differential expression of COX-1 and
`COX-2 in inflammation and their dramatically different
`responses to glucocorticoids is unclear, but the avail(cid:173)
`able data suggest that glucocorticoids affect the produc(cid:173)
`tion of proinflammatory arachidonic metabolites (37-40;
`Crofford LJ, Wilder RW, Hla T. Unpublished observa(cid:173)
`tions).
`
`Effects on Lymphocytes
`
`Dr. Dimitrios T. Boumpas: The immunosuppressive
`effects of glucocorticoids are also directed at the traffic
`and function of lymphocytes.
`
`T Lymphocytes
`
`In humans, a single dose of glucocorticoids produces
`a marked but transient lymphocytopenia involving all
`lymphocyte subpopulations (41). The mechanism of the
`lymphopenia involves the redistribution of circulating
`lymphocytes to other lymphoid compartments, particu(cid:173)
`larly the bone marrow (42). Changes in the expression
`of adhesion molecules (see Figure 3) may be responsible
`for that redistribution of lymphocytes (32). In contrast
`to other species (such as the mouse, rat, or rabbit),
`glucocorticoid-induced
`lymphopenia in humans is not
`due primarily to cell death. Mature, resting human lym(cid:173)
`phocytes are not lysed even by suprapharmacologic
`doses of glucocorticoids. However, immature human T
`cells (thymocytes and transformed lymphocytes) and, in
`some instances, activated T cells may be susceptible to
`lysis (43, 44) by programmed cell death (apoptosis).
`In addition to their effects on cell distribution, gluco(cid:173)
`corticoids also affect the initiation and the progression
`of the T-cell cycle. During the initiation phase (activa(cid:173)
`tion), antigen binds to the T-cell receptor and initiates a
`cascade of events that leads to production of interleu-
`kin-2 (and other cytokines) and induction of high-affinity
`interleukin-2 receptors. Binding of interleukin-2 to its
`receptor promotes T-cell proliferation and generation of
`effector, suppressor, and cytotoxic functions. As shown
`in Figure 4, glucocorticoids
`inhibit, through various
`mechanisms, several events associated with T-cell acti(cid:173)
`vation (45-48). In addition to depressing interleukin-2
`production, they interfere with the action of interleu-
`
`Figure 3. Cellular adhesion molecules. Several adhesion mole(cid:173)
`cules participate in the binding of leukocytes to endothelial
`cells (25, 26). These molecules belong to at least three groups
`of glycoproteins: immunoglobulin supergene families, integrins,
`and selectins. Members of the immunoglobulin supergene fam(cid:173)
`ily (intercellular cell adhesion molecule-1 [ICAM-1], vascular
`cell adhesion molecule-1 [VCAM-1]) are found exclusively on
`the endothelial cells. Their counter-receptors on
`leukocytes
`belong to the integrin group of adhesion molecules (lympho(cid:173)
`cyte (leukocyte) function-associated antigen-1 [LFA-1], very
`late antigen-4 [VLA-4]). Members of the selectin group (en(cid:173)
`dothelial
`leukocyte adhesion molecule-1
`[ELAM-1], sialyl
`Lewis X) group can be found in both cell types. These adhe(cid:173)
`sion molecules mediate the initial tethering and subsequent
`shear-resistant attachment of leukocytes to the endothelium as
`well as their penetration into the inflamed tissue. The cyto(cid:173)
`kines interleukin-1, tumor necrosis factor-a, and
`interferon-}
`are also involved in this process through the activation of
`endothelial cells and the induction of adhesion molecules on
`their surface. Activated endothelial cells secrete interleukin-8
`and other chemotactic cytokines that further stimulate the ex(cid:173)
`travasation of leukocytes bound to endothelial cells.
`
`hibit the secretion of the complement pathway proteins
`C3 and factor B; they also inhibit the formation of
`interleukin-1 and arachidonic acid metabolites and are
`potent inhibitors of the expression of cyclooxygenase
`type 2.
`
`Fibroblasts
`These cells contribute to the inflammatory process
`and are major targets of glucocorticoids (27). At supra-
`physiologic concentrations, glucocorticoids
`suppress
`proliferation and suppress growth factor-induced DNA
`synthesis and protein synthesis, including synthesis of
`collagens. They induce fibronectin messenger RNA tran(cid:173)
`scription, inhibit interleukin-1, inhibit tumor necrosis fac-
`tor-a-induced metalloproteinase synthesis, and
`inhibit
`arachidonic acid metabolite synthesis. They are also po(cid:173)
`tent inhibitors of the up-regulated expression of cyclooxy(cid:173)
`genase type 2 (Crofford LJ, Wilder RW, Hla T. Unpub(cid:173)
`lished observations). These observations suggest
`that
`glucocorticoids might retard bone and cartilage destruc(cid:173)
`tion in diseases such as rheumatoid arthritis.
`
`Prostaglandins
`The cellular actions of glucocorticoids may be af(cid:173)
`fected by prostaglandins. Prostaglandins are metabolites
`of arachidonic acid, which is released from phospho(cid:173)
`lipids by the action of phospholipase A2 Previously, it
`was assumed that glucocorticoids directly inhibited the
`enzymatic activity of this enzyme. New evidence, how(cid:173)
`ever, indicates that suppression of phospholipase A2
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`Figure 4. Nuclear factors involved in regulation of interleukin-2 gene expression. Binding of antigen to the T-cell antigen receptor
`(TCR)-CD3 complex stimulates the tyrosine phosphorylation of several intracellular proteins. This is followed by activation of
`protein kinase C (PKC) and by an increase in intracellular calcium (Ca2+) concentration, which then activates calcium-calmodulin-
`dependent kinases and phosphatases. The combination of these two signals (PKC and calcium) mediates the binding of nuclear
`proteins (transcription factors) to the interleukin (IL-2) gene promoter and initiates the transcription of the interleukin-2 gene. The
`newly synthesized interleukin-2 messenger RNA transcripts are transferred into the cytoplasm where they either are translated into
`the polyribosomes to the interkeukin-2 protein product (which is subsequently excreted) or are degraded by the RNAases.
`Glucocorticoids inhibit several steps during T-cell activation (indicated by the circled numbers). Thus, glucocorticoids inhibit the
`tyrosine phosphorylation (#7) but not the activation of PKC or the calcium influx (49). However, more distal sites in the calcium
`pathway (#2), such as the calcium-calmodulin kinase II, are inhibited (96). Binding of nuclear proteins (transcription factors) to the
`activated T cell (AT) (#i) and activator protein {AP)-\ (#4) sites of the human interleukin-2 promoter and its transcription activity
`are also inhibited by glucocorticoids (46, 47). This results in decreased production of interleukin-2 messenger RNA. Glucocorti(cid:173)
`coids also increase messenger RNA degradation (#5) (probably through the induction of RNAases), resulting in a profound
`decrease in interleukin-2 messenger RNA accumulation in ribosomes (#6) and a decrease in translation into protein product (#7)
`(45). Inhibition of interleukin-2 production requires low doses of glucocorticoids, whereas higher doses are required to inhibit
`interleukin-2 gene transcription suggesting that post-transcriptional mechanisms are also important for the inhibition of interleukin-2
`by glucocorticoids.
`
`kin-2 on activated T cells by inhibiting the interleukin-
`2-dependent phosphorylation of several
`intracellular
`proteins (48). Several other cytokines secreted by acti(cid:173)
`vated T cells (interleukins-3, -4, and -6 and interferon-y)
`are also inhibited by glucocorticoids (49, 50).
`Cytokines are essential for T-cell functions. Because
`glucocorticoids
`inhibit
`the production (and
`in some
`cases the action) of several cytokines, they also inhibit
`the function of T cells. Thus, the generation, prolifera(cid:173)
`tion, and function of helper and suppressor T cells are
`inhibited by
`these agents (51). Cytotoxic T-cell re(cid:173)
`sponses (both auto- and allo-reactive) are also inhibited
`by moderate-to-high doses of glucocorticoids, primarily
`because of the blockade of cytokine expression and to a
`lesser extent because of the lysis of reactive T-cell
`clones (52).
`
`B Lymphocytes
`
`In contrast to T cells, B cells are relatively resistant
`to the immunosuppressive effects of glucocorticoids.
`These agents inhibit the proliferation of B cells, pro(cid:173)
`vided that they are present in culture during the first 24
`hours after stimulation. Once B cells are activated, they
`
`differentiate into immunoglobulin-secreting plasma cells;
`glucocorticoids have only minimal effects on this pro(cid:173)
`cess (53).
`From a clinical standpoint, the most important effect
`of glucocorticoids on B cells relates to antibody produc(cid:173)
`tion. Low doses of glucocorticoids do not affect serum
`immunoglobulin
`levels or antibody synthesis in vivo
`after
`inoculation with various antigens, but a brief
`course of daily high-dose prednisone will decrease se(cid:173)
`rum immunoglobulin levels with maximal suppression
`observed 2 to 4 weeks after treatment (54). This sup(cid:173)
`pression is the result of an initial increase in immuno(cid:173)
`globulin catabolism, which is followed by decreased
`synthesis. The mechanisms for this decrease have not
`been defined. Because glucocorticoids inhibit the pro(cid:173)
`duction of several cytokines involved in immunoglobu(cid:173)
`lin synthesis (interleukins-1 through 6 and interferon-y),
`decreased immunoglobulin production could result from
`decreased accessory or helper T-cell activities. Whether
`glucocorticoids inhibit immunoglobulin gene expression
`is not known.
`traffic
`In summary, whereas inhibition of leukocyte
`and cellular immune responses require lower doses of
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`glucocorticoids, higher doses of these agents are needed
`to suppress the functions of leukocytes and the humoral
`immune response. This heterogeneity of response is
`also apparent among different persons and diseases (as
`described above).
`
`Therapeutic Use
`
`Dr. Thomas R. Cupps (Department of Medicine,
`Georgetown University Medical Center, Washington,
`D.C.): Glucocorticoid use should be based on an eval(cid:173)
`uation of therapeutic goals and benefits compared with
`potential drug-associated morbidity. Knowledge of the
`clinical pharmacology and treatment protocols of gluco(cid:173)
`corticoids is critical; several excellent reviews have
`been published (55-60).
`In general, topical or compartmental (for example,
`intra-articular) use of glucocorticoids results in less tox(cid:173)
`icity than does systemic administration. Among sys(cid:173)
`temic treatments involving the same total dose of glu(cid:173)
`cocorticoids, split-dose regimens are more toxic than
`single daily-dose protocols, which are themselves more
`toxic than alternate-day treatment schedules (42, 59).
`When administered on a daily basis, glucocorticoid an(cid:173)
`alogs with prolonged biologic half-lives (for example,
`dexamethasone) have a greater potential for side effects
`than do analogs with intermediate biologic half-lives (for
`example, prednisone). Higher doses of systemic gluco(cid:173)
`corticoids can be given for less than a week with rela(cid:173)
`tive safety, although the same dose of drug adminis(cid:173)
`tered
`for a more extended period will
`result
`in
`predictable, clinically significant morbidity.
`Patient education is an important factor in optimal
`glucocorticoid
`therapy. The patient should be made
`aware of the potential clinical consequences from hypo-
`thalamic-pituitary-adrenal (HPA) axis insufficiency that
`may result from systemic glucocorticoid therapy. Thus,
`the patient must be cautioned never to stop or rapidly
`taper glucocorticoids without medical advice. The HPA-
`axis response to stress may be decreased even after a
`week of daily glucocorticoid therapy (61). If regular oral
`glucocorticoid treatment is interrupted for a period of
`more than 24 hours, patients may be susceptible to
`circulatory collapse in response to physiologic stress,
`trauma, infection, or surgery, and parenteral adminis(cid:173)
`tration of glucocorticoids may be required. Even though
`HPA-axis insufficiency
`is more common with higher
`cumulative doses of glucocorticoids, it cannot be reli(cid:173)
`ably predicted from the dose of glucocorticoids, the
`duration of therapy, or the basal plasma Cortisol levels.
`Testing with corticotrophin-releasing hormone may be
`useful
`in assessing pituitary-adrenal functions
`in pa(cid:173)
`tients who may have HPA-axis insufficiency (62).
`The patient should be warned
`that glucocorticoid
`therapy usually stimulates
`the appetite and causes
`weight gain; thus, the importance of diet should be
`emphasized when therapy is begun. The symptoms and
`signs of diabetes and steroid myopathy, as well as neu-
`ropsychiatric and
`infectious complications associated
`with glucocorticoid therapy, should also be described to
`the patient (63).
`The choice of a particular glucocorticoid analog for
`systemic therapy depends, in part, on clinical variables.
`
`is generally used for physiologic re(cid:173)
`Hydrocortisone
`placement and "stress" coverage if patients have HPA
`suppression (64). Because of its short biologic half-life
`and sodium- and potassium-retaining effects, this agent
`is not commonly used for systemic immunosuppressive
`or anti-inflammatory
`treatment. Fluorinated analogs,
`such as dexamethasone,