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60 Glucocorticoid Therapy JOHANNES W.G. JACOBS • JOHANNES W.J. BIJLSMA KEY POINTS Mode of action of glucocorticoids is genomic (via glucocorticoid receptor) and, in high dosages, also nongenomic. Glucocorticoids differ considerably in potency and biologic half-life. Cortisone and prednisone are biologically inactive and are converted in the liver into biologically active cortisol and prednisolone. Glucocorticoids have disease-modifying properties in early rheumatoid arthritis. The risk of adverse effects of a glucocorticoid is patient, dose, and time dependent. The risk of adverse effects of low-dose glucocorticoids generally is overestimated. After local injection of a glucocorticoid, the risk of local bacterial infection is very low. Low and low-to-moderate doses of prednisolone in pregnancy appear to be safe. Glucocorticoids are widely used for the treatment of patients with rheumatic disease. The first to be isolated, in 1935, was the naturally occurring glucocorticoid hormone, cortisone. It was synthesized in 1944 and subsequently became available for clinical use. In 1948, cortisone (then called compound E) was administered by the American physician Philip S. Hench to a 29-year-old woman with active rheumatoid arthritis (RA) of longer than 4 years’ duration. Her joints were so painful she could “hardly get out of bed.” After 2 days of treatment with 100 mg of intramuscular compound E daily, “She rolled over in bed with ease, and noted much less muscular soreness.” The next day, she was able to walk with “only a slight limp.” Hench published this case of dramatic improvement in 19491 and won the 1950 Nobel Prize in Physiology or Medicine for his research, which he shared with two colleagues at the Mayo Clinic. Later, by chemical modification of natural steroids, different synthetic glucocorticoids were produced, some of which have proved to be very effective anti-inflammatory and immunosuppressive substances with rapid, sometimes instant, effects. Initially, there was considerable enthusiasm about glucocorticoid therapy because of the striking relief of symptoms seen in patients treated with supraphysiologic dosages. When the wide array of potentially serious adverse side 894 effects became apparent, however, the use of glucocorticoids decreased. Nevertheless, because glucocorticoids can be considered the most effective anti-inflammatory and immunosuppressive substances currently known, they have become a cornerstone of therapy for many rheumatic disorders, including systemic lupus erythematosus (SLE), vasculitis, polymyalgia rheumatica, and myositis. The use of glucocorticoids in therapeutic strategies for patients with RA has become accepted. During past decades, knowledge about glucocorticoids has increased, but much remains to be learned about the modes of actions of these drugs in rheumatic autoimmune disorders. It is hoped that the unraveling of these mechanisms eventually may lead to new applications of glucocorticoids or novel classes of therapy. CHARACTERISTICS OF GLUCOCORTICOIDS Structure and Classification The precursor molecule of all steroid hormones is cholesterol, which is also a building block for vitamin D and cell membranes and organelles (Figure 60-1). Steroid hormones and cholesterol are characterized by a sterol skeleton, formed by three six-carbon hexane rings and one fivecarbon pentane ring. The carbon atoms of this sterol nucleus are numbered in a specific sequence; the term steroid refers to this basic sterol nucleus (Figure 60-2). Steroid hormones can be classified on the basis of their main function into sex hormones (male and female), mineralocorticoids, and glucocorticoids. Sex hormones are synthesized mainly in the gonads, but also in the adrenal cortex. Mineralocorticoids and glucocorticoids are synthesized only in the adrenal cortex; the terms corticosteroid and corticoid for these hormones refer to the adrenal cortex. Some glucocorticoids also have a mineralocorticoid effect and vice versa. The main natural mineralocorticoid is aldosterone, and the main natural glucocorticoid is cortisol (hydrocortisone). Although separation of corticoids into the classes mineralocorticoids and glucocorticoids is not absolute (see later), it is better (more precise) to use the term glucocorticoid than the term corticosteroid when referring to one of these compounds.2 The importance of standardized nomenclature is illustrated by the fact that an electronic literature search can be complicated by multiple synonyms. In the 1950s, chemical modification of natural steroids revealed numerous structural features essential for specific biologic activities. Synthetic steroid hormones more potent than natural steroid hormones and steroid hormones with CHAPTER 60 | Glucocorticoid Therapy 895 Cholesterol OH Cell membranes, myelin Steroid hormones: • Glucocorticoids • Mineralocorticoids • Male sex hormones • Female sex hormones Vitamin D Cellular organelles Figure 60-1 Cholesterol as building block for steroid hormones, vitamin D, and cell membranes and organelles. altered biologic activity were developed. This research showed that the 17-hydroxy, 21-carbon steroid configuration (see Figure 60-2) is required for glucocorticoid activity through binding to the glucocorticoid receptor. Glucocorticoids with an 11-keto, instead of an 11-hydroxy, group, such as cortisone and prednisone, are prohormones that must be reduced in the liver to their 11-hydroxy configurations. Cortisone is converted by hepatic pathways to cortisol, and prednisone is converted to prednisolone, to become biologically active. Thus in patients with severe liver disease, it is rational to prescribe prednisolone instead of prednisone. The generation of biologically active glucocorticoids from their inactive forms is promoted by the reductase action of the intracellular enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1. The same enzyme can by dehydrogenation promote the reverse reaction, leading to inactivation of active glucocorticoids. In contrast, 11βHSD type 2 has dehydrogenase activity only, so it catalyzes only the conversion of active glucocorticoids to their inactive forms. In different tissues, local balance between the intracellular enzymes 11β-HSD type 1 and type 2 might modulate intracellular glucocorticoid concentrations and thus tissue sensitivity for glucocorticoids.3 Synovial tissue metabolizes glucocorticoids via the two 11β-HSD enzymes, with the net effect being glucocorticoid activation; this increases with inflammation. This endogenous glucocorticoid production in the joint is likely to have an impact on local inflammation and on bone in the joint.4 No qualitative differences have been noted between the glucocorticoid effect of endogenous cortisol and that of exogenously applied synthetic glucocorticoids because these effects are, except for higher doses, predominantly genomic (i.e., mediated through the glucocorticoid receptor).5 However, quantitative differences have been identified. The potency and other biologic characteristics of glucocorticoids depend on structural differences in the steroid configuration. The introduction of a double bond between the 1 and 2 positions of cortisol yields prednisolone, which has about four times more glucocorticoid activity than cortisol (Table 60-1). Addition of a six-methyl group to prednisolone yields methylprednisolone, which is about five times more potent than cortisol. All the aforementioned glucocorticoids also have a mineralocorticoid effect. The synthetic glucocorticoids triamcinolone and dexamethasone have negligible mineralocorticoid activity, however. Biologic Characteristics and Therapeutic Consequences Apart from the steroid configuration, biologic characteristics of glucocorticoids also depend on whether they are in free form (as alcohol) or are chemically bound (as ester or salt). In their free form, glucocorticoids are virtually insoluble in water, so they can be used in tablets but not in parenteral preparations. For this reason, synthetic glucocorticoids are formulated as organic esters or as salts. Esters, such as (di)acetate and (hex)acetonide, are lipid soluble but have limited water solubility and are suitable for oral use and intramuscular, intralesional, and intra-articular injection. Salts, such as sodium phosphate and sodium succinate, are generally more water soluble and thus are also suitable for intravenous use. Dexamethasone sodium phosphate can be used intravenously, whereas dexamethasone acetate cannot. When given intramuscularly, dexamethasone sodium phosphate is absorbed much faster from the injection site than dexamethasone acetate. If an immediate effect is required, dexamethasone sodium phosphate given intravenously is more rapidly effective than the same preparation given intramuscularly; the least rapidly active is that of intramuscular dexamethasone acetate. For local use, less solubility means longer duration of the local effect, which generally is beneficial. 896 PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS OH 1 17 12 11 13 16 14 15 9 8 10 2 3 Basic sterol nucleus Cholesterol 7 6 5 21 CH2OH 4 20 C 11 19 1 C OH 17 12 CH2OH O 18 O OH 13 16 14 15 OH OH 9 8 10 2 3 Cortisol (hydrocortisone) Cortisone 7 5 O O 6 O CH2OH 4 C CH2OH C O OH O OH OH Prednisolone Prednisone O O CH2OH C O CH2OH C O OH OH O OH OH OH F Methylprednisolone Triamcinolone O O CH3 CH2OH C CH2OH O C OH OH CH3 F Dexamethasone O OH OH CH3 F O Betamethasone O Figure 60-2 Basic steroid configuration and structure of cholesterol and of natural and some synthetic glucocorticoids. Structural differences of glucocorticoids compared with cortisol, the natural active glucocorticoid, are shown in red. Pharmacokinetics and Pharmacology Water insolubility does not impair absorption from the digestive tract. Most orally administered glucocorticoids, whether in free form or as an ester or salt, are absorbed readily, probably within about 30 minutes. Bioavailability of prednisone and prednisolone is high. Commercially available oral and rectal prednisone and prednisolone preparations are considered approximately bioequivalent. The affinity of the different glucocorticoids for various plasma proteins varies (see Table 60-1). Of cortisol in plasma, 90% to 95% is bound to plasma proteins, primarily CHAPTER 60 | Glucocorticoid Therapy 897 Table 60-1 Pharmacodynamics of Commonly Used Glucocorticoids Equivalent Glucocorticoid Dose (mg) Relative Glucocorticoid Activity Relative Mineralocorticoid Activity* Protein Binding 0.8 1 0.8 1 − ++++ 0.5 1.5-2 5 4 4 5 0.5 0.6 0.6 0 − ++ +++ ++ >3.5 2.1-3.5 3.4-3.8 2->5 18-36 18-36 18-36 18-36 0 0 ++ ++ 3-4.5 3-5 36-54 36-54 Plasma Half-Life Biologic Half-Life (hr) Short-Acting Cortisone Cortisol 25 20 8-12 8-12 Intermediate-Acting Methylprednisolone Prednisolone Prednisone Triamcinolone 4 5 5 4 Long-Acting Dexamethasone Betamethasone 0.75 0.6 20-30 20-30 *Clinically; sodium and water retention, potassium depletion. −, None; ++, high; +++, high to very high; ++++, very high. transcortin (also called corticosteroid-binding globulin) and, to a lesser degree, albumin. Protein-bound cortisol is not biologically active, but the remaining 5% to 10% of free cortisol is. Prednisolone has—in contrast to methylprednisolone, dexamethasone, and triamcinolone—a high affinity for transcortin and competes with cortisol for this binding protein. The other synthetic glucocorticoids with little or no affinity for transcortin are two-thirds (weakly) bound to albumin, and about one-third circulate as free glucocorticoid. Because only unbound glucocorticoids are pharmacologically active, patients with low levels of plasma protein, such as albumin (e.g., because of liver diseases or chronic active inflammatory diseases), are more susceptible to effects and side effects of glucocorticoids. Dosage adjustment should be considered in these patients. In liver disease, an additional argument for dosage adjustment is reduced clearance of glucocorticoids (see later). Glucocorticoids have biologic half-lives 2 to 36 times longer than their plasma half-lives (see Table 60-1). With a plasma half-life of about 3 hours, prednisolone can be dosed once daily for most diseases. Maximal effects of glucocorticoids lag behind peak serum concentrations. Transcortin binds these compounds more strongly than does albumin. The plasma elimination of glucocorticoids bound to transcortin is slower than that of glucocorticoids that do not bind. Transcortin binding is not a major determinant of biologic half-lives of glucocorticoids, however, in contrast to distribution to different compartments of the body and binding to the cytosolic glucocorticoid receptor. Synthetic glucocorticoids have lower affinity for transcortin but higher affinity for the cytosolic glucocorticoid receptor than does cortisol (see later). The affinity of prednisolone and triamcinolone for the glucocorticoid receptor is approximately two times higher, and for dexamethasone it is seven times higher. Prednisone and cortisone have had negligible glucocorticoid bioactivity before they have been chemically reduced because of their very low affinity for the glucocorticoid receptor. Another important factor determining biologic half-lives of glucocorticoids is the rate of metabolism. Synthetic glucocorticoids are subject to the same reduction, oxidation, hydroxylation, and conjugation reactions as cortisol. Pharmacologically active glucocorticoids are metabolized primarily in the liver into inactive metabolites and are excreted by the kidneys; only small amounts of unmetabolized drug are also excreted in the urine. An inverse correlation has been noted between prednisolone clearance and age, which means that a given dose may have a greater effect in older individuals.6 Prednisolone clearance also is slower in African-Americans compared with that in whites.7 The serum half-life of prednisolone is 2.5 to 5 hours, but it is increased in patients with renal disease and liver cirrhosis, and in the elderly. Prednisolone can be removed by hemodialysis, but overall, the amount removed does not require dosage adjustment in patients on hemodialysis. In patients with cirrhosis of the liver, clearance of unbound steroid is about two-thirds of normal—a difference that should be taken into account with dosing. Drug Interactions Cytochrome P450 (CYP) is a family of isozymes responsible for the biotransformation of several drugs. Drug interactions can be based on induction or on inhibition of these enzymes. Certain drugs (e.g., barbiturates, phenytoin, rifampin) by inducing CYP isoenzymes (e.g., CYP3A4) increase the metabolism (breakdown) of synthetic and natural glucocorticoids, particularly by enhancing hepatic hydroxylase activity, thus reducing glucocorticoid concentrations (Figure 60-3). Rifampin-induced nonresponsiveness to prednisone in inflammatory diseases indeed has been described,8,9 as has rifampin-induced adrenal crisis in patients on glucocorticoid replacement therapy.10 Clinicians should consider increasing the dosage of glucocorticoids in patients who are concomitantly treated with these medications. Conversely, concomitant use of glucocorticoids with inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, diltiazem, mibefradil and grapefruit juice) decreases glucocorticoid clearance and leads to higher concentrations and prolonged biologic half-lives of glucocorticoid drugs, thus increasing the risk of adverse effects.11 Antifungal therapies, especially ketoconazole, on the other hand are known to interfere with endogenous glucocorticoid synthesis and therefore are also used, in doses of 400 to 800 mg per day, to treat hypercortisolism.11 Etomidate, a Serum prednisolone concentraton (ng/nL) 898 PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS 800 600 Without rifampin 400 With rifampin 200 0 0 6 12 Time (h) 18 24 Figure 60-3 Serum prednisolone concentration in time in one patient, after 0.9 mg/kg prednisone orally daily, in the presence and absence of therapy with rifampin. Curve with rifampin, during a period of continuous administration of both drugs. Curve without rifampin, after a washout of rifampin of 4 weeks. Rifampin induces a reduced area under the curve of prednisolone, indicating reduced bioavailability.8 short-acting intravenous anesthetic agent used for the induction of general anesthesia and for sedation, can also lower cortisol levels, which could be clinically relevant in critically ill patients.11 Concomitant administration of prednisolone and cyclosporine may result in increased plasma concentrations of the former drug; concomitant administration of methylprednisolone and cyclosporine may result in increased plasma concentrations of the latter drug. The mechanism of this probably is competitive inhibition of microsomal liver enzymes. Antibiotics such as erythromycin may increase plasma concentrations of glucocorticoids. Synthetic estrogens in oral contraceptives increase the level of transcortin and thus total (sum of bound and unbound) glucocorticoid levels. Therefore, in women taking oral contraceptives, care is required in the interpretation of cortisol measurements, especially because adrenal insufficiency may be present even when total cortisol levels are within the normal range.12 Next to glucocorticoids, other steroid drugs such as megestrol acetate and medroxyprogesterone inhibit the hypothalamic-pituitary-adrenal axis11; this risk may be increased when they are used concomitantly with glucocorticoids. Sulfasalazine has been reported to increase the sensitivity of immune cells for glucocorticoids,13 which could be beneficial. maternal-to-fetal dexamethasone blood concentration ratio is about 1 : 1. If a pregnant woman has to be treated with glucocorticoids, prednisone, prednisolone, and methylprednisolone would be good choices; if the unborn child has to be treated, fluorinated glucocorticoids, such as betamethasone or dexamethasone, would be indicated. Fear of physical (e.g., reduced growth) and neurocognitive adverse effects in children exposed to antenatal repeat doses of 12 mg betamethasone has not been substantiated,14,15 in contrast to postnatal glucocorticoid exposure.16 However, because of a small but increased risk of an oral cleft, it is advised to avoid high doses (1 to 2 mg/kg prednisone equivalent) in the first trimester of pregnancy,17,18 whereas low to moderate doses of prednisone seem to be safe.18 Prednisolone and prednisone are excreted in small quantities in breast milk. Breastfeeding is generally considered safe for an infant whose mother is taking these drugs. Because curves of milk and serum concentrations for prednisolone are virtually parallel in time, exposure of the infant is minimized if breastfeeding is avoided during the first 4 hours after the intake of prednisolone.18 BASIC MECHANISMS OF GLUCOCORTICOIDS Genomic and Nongenomic Effects Glucocorticoids at any therapeutically relevant dosage exhibit pharmacologic effects via classic genomic mechanisms. The lipophilic glucocorticoid passes across the cell membrane, attaches to the cytosolic glucocorticoid receptor and heat shock protein, and binds to glucocorticoidresponsive elements on genomic DNA; it interacts with nuclear transcription factors. This process takes time. When acting through genomic mechanisms, it takes at least 30 minutes before the clinical effect of a glucocorticoid begins to show.19 Only when high doses are given, as in pulse therapy, can glucocorticoids act within minutes by nongenomic mechanisms; this occurs via specific receptormediated activity or via nonspecific membrane-associated physicochemical activity.5 The response to high-dose pulse methylprednisolone therapy may be biphasic, consisting of an early, rapid, nongenomic effect and a delayed and more sustained classic genomic effect.20 Clinically, genomic and nongenomic effects cannot be separated, however. Pregnancy and Lactation Genomic Mechanisms In pregnancy, two mechanisms protect the fetus from exogenous glucocorticoids. First, glucocorticoids bound to transport proteins cannot pass the placenta, in contrast to unbound glucocorticoids. Second, the enzyme 11β-HSD in the placenta, which catalyzes the conversion of active cortisol, corticosterone, and prednisolone into the inactive 11-dehydro-prohormones (cortisone, 11dehydrocorticosterone, and prednisone), protects the fetus from glucocorticoids in the blood of the mother. The maternal-to-fetal prednisolone blood concentration ratio is about 10 : 1, owing to these mechanisms. In contrast, dexamethasone has little or no affinity for transport proteins and is poorly metabolized by 11β-HSD in the placenta; the Most of the effects of glucocorticoids are exerted via genomic mechanisms by binding to the glucocorticoid receptor located in the cytoplasm of the target cells; glucocorticoids are lipophilic and have a low molecular mass; thus they can pass through the cell membrane easily. Next to the tissuespecific intracellular density of glucocorticoid receptors, the balance of intracellular 11β-HSDs (see earlier) probably determines the sensitivity of specific tissues for glucocorticoids.3 Of the isoforms α and β of the glucocorticoid receptor, only the α isoform, common in all target tissues, binds to glucocorticoids.19 This is a 94-kD protein to which several heat shock proteins (chaperones) are bound. Binding of the glucocorticoid to this complex causes shedding of CHAPTER 60 the chaperones. The resulting activated glucocorticoid receptor–glucocorticoid complex is rapidly translocated into the nucleus, where it binds (as a dimer) to specific consensus sites in the DNA (glucocorticoid-responsive elements), regulating the transcription of a large variety of target genes. This process is termed transactivation. Binding to glucocorticoid-responsive elements results in stimulation or suppression of transcription of these target genes. Suppression of genes also may be mediated by mechanisms involving interaction of the glucocorticoid receptor–glucocorticoid complex (as a momomer) with transcriptional factors, such as activator protein-1 and nuclear factor κB.21 This process is termed transrepression (Figure 60-4). The nature and availability of these transcription factors may be pivotal in determining the differential sensitivity of different tissues to glucocorticoids because they play a crucial role in regulating the expression of a wide variety of proinflammatory genes induced by cytokines. The binding of transcriptional factors to DNA is inhibited by glucocorticoids, resulting in depressed expression of these genes and inhibition of their amplifying role in inflammation. Activated glucocorticoid receptors also may inhibit protein synthesis by decreasing the stability of mRNA through the induction of ribonucleases. This mechanism has been proposed to mediate glucocorticoid-induced inhibition of the synthesis of interleukin (IL)-1, IL-6, granulocytemacrophage colony-stimulating factor, and inducible cyclooxygenase (COX)-2.22 There is increasing acceptance of the hypothesis that side effects of glucocorticoids, such as diabetes mellitus, osteoporosis, skin atrophy, growth retardation, and cushingoid appearance, may be based predominantly on transactivation of genes after binding of glucocorticoid receptor–glucocorticoid to DNA, whereas the antiinflammatory effects may be due mostly to the binding of a single glucocorticoid receptor-glucocorticoid complex to Glucocorticoid Therapy 899 transcription factors or co-activators, resulting in gene repression (transrepression). Understanding of these molecular mechanisms may lead to development of novel glucocorticoids, such as selective glucocorticoid receptor agonists, with a more favorable balance of transactivation and transrepression and, clinically, to a more favorable balance of metabolic and endocrine side effects and therapeutic effects21 (see later). Expression of multiple target genes at the posttranscriptional level, also those influenced by glucocorticoids, is modulated by microRNAs (miRNAs), short noncoding RNA molecules that are implicated in a wide array of cellular and immune processes. Abnormal expression of miRNAs has been found in patients with rheumatoid arthritis. This identifies miRNAs as targets for immunomodulatory drug development.23 Glucocorticoid Effects on the Immune System Glucocorticoids reduce activation, proliferation, differentiation, and survival of a variety of inflammatory cells, including macrophages and T lymphocytes, and promote apoptosis, especially in immature and activated T cells (Figure 60-5). This activity is mediated mainly by changes in cytokine production and secretion. In contrast, B lymphocytes and neutrophils are less sensitive to glucocorticoids, and their survival may be increased by glucocorticoid treatment. The main effect of glucocorticoids on neutrophils seems to be inhibition of adhesion to endothelial cells. Glucocorticoids inhibit not only the expression of adhesion molecules, but also the secretion of complement pathway proteins and prostaglandins. At supraphysiologic concentrations, glucocorticoids suppress fibroblast proliferation and IL-1 and tumor necrosis factor (TNF)-induced metalloproteinase synthesis. By these effects, glucocorticoids may retard bone and cartilage destruction in the inflamed joint.24 Glucocorticoid responsive Cell membrane Cytoplasm element Glucocorticoid | Nucleus Nuclear membrane mRNA Glucocorticoid receptor Up-regulated synthesis of proteins Transactivation Transrepression No binding Transcription factor NFκB No mRNA DNA Down-regulated synthesis of proteins NFκB responsive element Figure 60-4 Genomic action of glucocorticoids. Glucocorticoid binds to the glucocorticoid receptor in the cytoplasm. This complex migrates into the nucleus. Activation of transcription (transactivation) by binding of glucocorticoid receptor–glucocorticoid dimers to glucocorticoid-responsive elements of DNA up-regulates synthesis of regulatory proteins, thought to be responsible for metabolic effects and also some anti-inflammatory/ immunosuppressive effects. Interference of glucocorticoid receptor–glucocorticoid monomers with proinflammatory transcription factors, such as nuclear factor κB (NFκB), inhibits their binding to NFκB-responsive elements of DNA and transcription. This is called transrepression and down-regulates synthesis of predominantly inflammatory/immunosuppressive proteins. 900 PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS ↑ Apoptosis ↑ Apoptosis Tc cell Th cell ↓ IL-1β ↓ IL-12 ↓ TNF Macrophage ↑ Apoptosis ↑ Apoptosis ↑ IL-10 (↓ Antibodies at very high GC doses) Dendritic cell ↑ IL-4 B cell line ↓ Cytotoxicity Glucocorticoids NK cell Fibroblast Tc cell Th cell ↓ IFN-γ ↓ IL-2 Neutrophil ↓ Proliferation ↓ Fibronectin ↓ Prostaglandins ↓ Migration ↑ Apoptosis ↑ Apoptosis Figure 60-5 Effects shown in red type. Downregulation of adhesion molecules decreases migration of neutrophils and increases the number of circulating neutrophils. GC, glucocorticoid; IFN-γ, interferon-γ; IL, interleukin; NK, natural killer; Tc, cytotoxic T lymphocyte; Th, helper T lymphocyte; TNF, tumor necrosis factor. (Modified from Sternberg E: Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens, Nat Rev Immunol 6:318–328, 2006.) Leukocytes and Fibroblasts Administration of glucocorticoids leads to an increase in the total leukocyte count caused by an increase in circulating neutrophil granulocytes in the blood, although the numbers of other leukocyte subsets in blood such as eosinophil and basophil granulocytes, monocytes/macrophages (decreased myelopoiesis and bone marrow release), and T cells (redistribution effect) are decreased. Table 60-2 summarizes the effects of glucocorticoids on leukocyte subsets. The redistribution of lymphocytes, which is maximal 4 to 6 hours after administration of a single high dose of prednisone and returns to normal within 24 hours, has no clinical consequences. B cell function and immunoglobulin production are hardly affected. The effects of glucocorticoids on monocytes and macrophages, including decreased expression of major histocompatibility complex (MHC) class II molecules and Fc receptors, may increase susceptibility to infection, however.25 Effects of glucocorticoids on fibroblasts include decreased proliferation and decreased production of fibronectin and prostaglandins. glucocorticoid action in chronic inflammatory diseases such as RA. Glucocorticoids exert potent inhibitory effects on the transcription and action of a large variety of cytokines with pivotal importance in the pathogenesis of RA. Most T helper type 1 (Th1) proinflammatory cytokines are inhibited by glucocorticoids, including IL-1β, IL-2, IL-3, IL-6, Table 60-2 Anti-inflammatory Effects of Glucocorticoids on Immune Cells Cell Type Effects Neutrophils Increased blood count, decreased trafficking, relatively unaltered functioning Decreased blood count, decreased trafficking, decreased phagocytosis and bactericidal effects, inhibited antigen presentation, decreased cytokine and eicosanoid release Decreased blood count, decreased trafficking, decreased cytokine production, decreased proliferation and impaired activation, little effect on immunoglobulin synthesis Decreased blood count, increased apoptosis Decreased blood count, decreased release of mediators of inflammation Macrophages and monocytes Lymphocytes Cytokines Eosinophils The influence of glucocorticoids on cytokine production and action represents one of the major mechanisms of Basophils CHAPTER 60 TNF, interferon-γ (indicative of Th1 helper cells), IL-17 (indicative of Th17 helper cells), and granulocytemacrophage colony-stimulating factor (see Figure 60-5). In RA, these cytokines are considered responsible for synovitis, cartilage degradation, and bone erosion. Conversely, the production of Th2 cytokines, such as IL-4, IL-10, and IL-13, may be stimulated or not affected by glucocorticoids (see Figure 60-5).26 These cytokines have been related to the extra-articular features of erosive RA associated with B cell overactivity, such as immune complex formation and vasculitis. Activation of Th2 cells can suppress rheumatoid synovitis and joint destruction through release of the antiinflammatory cytokines IL-4 and IL-10, which inhibit Th1 activity and downregulate monocyte and macrophage functions.27 Inflammatory Enzymes An important part of the inflammatory cascade is arachidonic acid metabolism, which leads to the production of prostaglandins and leukotrienes, most of which are strongly proinflammatory. Through the induction of lipocortin (an inhibitor of phospholipase A2), glucocorticoids inhibit the formation of arachidonic acid metabolites. Glucocorticoids also have been shown to inhibit the production of COX-2 and phospholipase A2 induced by cytokines in monocytes/ macrophages, fibroblasts, and endothelial cells. In addition, glucocorticoids are potent inhibitors of the production of metalloproteinases in vitro and in vivo, especially collagenase and stromelysin, which are the main effectors of cartilage degradation induced by IL-1 and TNF.28 Adhesion Molecules and Permeability Factors Pharmacologic doses of glucocorticoids dramatically inhibit exudation of plasma and migration of leukocytes into inflammatory sites. Adhesion molecules play a central role in chronic inflammatory diseases by controlling the trafficking of inflammatory cells into sites of inflammation. Glucocorticoids reduce the expression of adhesion molecules through inhibition of proinflammatory cytokines and by direct inhibitory effects on the expression of adhesion molecules, such as intercellular adhesion molecule-1 and E-selectin.29 Chemotactic cytokines attracting immune cells to the inflammatory site, such as IL-8 and macrophage chemoattractant proteins, also are inhibited by glucocorticoids. Nitric oxide production in inflammatory sites is increased by proinflammatory cytokines, resulting in increased blood flow, exudation, and probably amplification of the inflammatory response. The inducible form of nitric oxide synthase by cytokines is potently inhibited by glucocorticoids.30 Hypothalamic-Pituitary-Adrenal Axis Pathophysiology Proinflammatory cytokines, such as IL-1 and IL-6, and eicosanoids, such as prostaglandin E2, and endotoxins all activate corticotropin-releasing hormone (CRH) at the hypothalamic level (Figure 60-6). This activation stimulates the secretion of adrenocorticotropic hormone (ACTH) | Glucocorticoid Therapy 901 by the pituitary gland and of glucocorticoids by the adrenal glands. In otherwise healthy individuals with severe infection or other major physical stress, cortisol production may increase to six times the normal amount.12 In patients with active RA (or other chronic inflammatory diseases), the increase in cortisol driven by elevated cytokines might be inappropriately low,31 meaning that cortisol levels— although normal or elevated in the absolute sense—are insufficient to control the inflammatory response. This is the concept of relative adrenal insufficiency.31-33 En dogenous and exogenous glucocorticoids exert negative feedback control on the hypothalamic-pituitary-adrenal axis directly by suppressing secretion of ACTH and CRH, and indirectly by suppressing release from inflammatory tissues of proinflammatory cytokines, which stimulate secretion of ACTH and CRH (see Figure 60-6). Sensitivity of the hypothalamic-pituitary-adrenal axis for proinflammatory cytokines is probably decreased in RA.34 ACTH is secreted in brief, episodic bursts, resulting in sharp increases in plasma concentrations of ACTH and cortisol, followed by slower declines in cortisol levels—the normal diurnal rhythm in cortisol secretion. Secretory ACTH episodic bursts increase in amplitude but not in frequency after 3 to 5 hours of sleep, reach a maximum during the hours before and the hour after awakening, decline throughout the morning, and are minimal in the evening. Cortisol levels are highest at about the time of awakening in the morning, are low in the late afternoon and evening, and reach their lowest level some hours after falling asleep (see Figure 60-6). Glucocorticoids are not stored in the adrenal glands in significant quantities. Continuing synthesis and release are required to maintain basal secretion or to increase blood levels during stress. The total daily basal or physiologic secretion of cortisol in humans has been estimated to range from 5.7 to 10 mg/m2/ day.35,36 This would be covered in primary adrenal insufficiency by oral administration of 15 to 25 mg cortisol,35 equivalent to about 4 to 6 mg prednisone. This low daily cortisol production rate may explain the cushingoid symptoms and other adverse effects that are sometimes observed in patients with adrenal insufficiency who are using glucocorticoids at doses previously regarded to be replacement doses (based on estimates of physiologic secretion of cortisol of 12 to 15 mg/m2/day), which are in fact supraphysiologic doses. Effects of Glucocorticoids on the HypothalamicPituitary-Adrenal Axis Chronic suppression of the hypothalamic-pituitary-adrenal axis by administration of exogenous glucocorticoids leads by negative feedback loops on CRH and ACTH (see Figure 60-6) to failure in pituitary ACTH release, and thus to partial functional adrenal atrophy with loss of cortisol secretory capability in the fasciculata-reticularis zone. This inner cortical zone is the site of cortisol and adrenal androgen synthesis and is dependent on ACTH for structure and function. The outer cortical (glomerulosa) zone is involved in mineralocorticoid (aldosterone) biosynthesis and is functionally independent of ACTH. It stays functionally intact. Patients have failure of pituitary ACTH release and adrenal 902 PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS Psychological and Cerebral physical stress circadian clock Hypothalamus CRH - Cytokines, e.g., IL-1, IL-6 - Endotoxines - Other mediators of inflammation ACTH Pituitary anterior lobe Arthritis and other inflammatory processes Cortisol Exogenous glucocorticoids Cortisol levels in RA IL-6 levels in RA Cortisol levels in controls Early morning stiffness in RA 22.00 24.00 02.00 04.00 06.00 08.00 10.00 Figure 60-6 Upper part, Stimulation (plus signs) and inhibition (minus signs) of the hypothalamic-hypopituitary-adrenal axis. Lower part, On the x-axis hours, plasma cortisol levels (blue line) in rheumatoid arthritis (RA) show an earlier and higher circadian rise compared with those in healthy controls, possibly caused by the rise in the proinflammatory cytokine interleukin-6 (IL-6); this rise is absent in healthy controls. IL-6 stimulates the hypothalamus and thus the release of cortisol, but probably also contributes to early morning stiffness and other inflammatory symptoms in (rheumatoid) arthritis. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone. CHAPTER 60 responsiveness to ACTH. Serum cortisol, ACTH levels, and adrenal responsiveness to ACTH are low, but other pituitary axes function normally, in contrast to the situation in most primary pituitary disorders. The time required to achieve suppression depends on the dosage and the serum half-life of the glucocorticoid used, but it also varies among patients, probably because of individual differences in glucocorticoid sensitivity and rates of glucocorticoid metabolism. Prediction with certainty of chronic suppression of the hypothalamic-pituitary-adrenal axis and adrenal insufficiency is impossible. This risk may be increased when glucocorticoids are used concomitantly with other steroid drugs such as megestrol acetate and medroxy progesterone, inhibiting the hypothalamic-pituitaryadrenal axis.11 The duration of the anti-inflammatory effect of one dose of a glucocorticoid approximates the duration of hypothalamic-pituitary-adrenal suppression. After a single oral dose of 250 mg of hydrocortisone or cortisone, 50 mg of prednisone or prednisolone, or 40 mg of methylprednisolone, suppression for 1.25 to 1.5 days has been described. Duration of suppression after 40 mg of triamcinolone and 5 mg of dexamethasone was 2.25 and 2.75 days.37 After intramuscular administration of a single dose of 40 to 80 mg of triamcinolone acetonide, the duration of hypothalamicpituitary-adrenal suppression is 2 to 4 weeks, and after 40 to 80 mg of methylprednisolone, suppression lasts 4 to 8 days.37 In the case of long-term therapy, for patients who have had less than 10 mg of prednisone or its equivalent per day in one dose in the morning, the risk of clinical (symptomatic) adrenal insufficiency is not high, but neither is it negligible. A review of adrenal insufficiency stated that if the daily dose is 7.5 mg of prednisolone or equivalent or more for at least 3 weeks, adrenal hypofunction should be anticipated, and acute cessation of glucocorticoid in this situation could lead to problems.12 Patients who have received glucocorticoids for less than 3 weeks or have been treated with alternate-day prednisolone therapy do not have zero risk of suppression of the hypothalamic-pituitaryadrenal axis, depending on the dose,38,39 but the risk is low. After 5 to 30 days of at least 25 mg of prednisone or equivalent daily, suppression of adrenal response (measured by a low-dose corticotropin test) was present in 34 of 75 patients studied (45%).40 In these patients, a basal plasma cortisol concentration less than 100 nmol/L was highly suggestive of adrenal suppression, whereas levels of basal cortisol greater than 220 nmol/L predicted a normal adrenal response in most, but not all, patients. When in doubt, it seems prudent to treat patients as having secondary adrenal insufficiency. Secondary adrenal insufficiency generally has a less dramatic presentation than primary adrenal insufficiency because aldosterone levels, which are controlled predominantly by the renin-angiotensin system, are preserved; mineralocorticoid therapy is not necessary. TREATMENT WITH GLUCOCORTICOIDS Glucocorticoids are widely used in various dosages for several rheumatic diseases. Often it is unclear what is meant by the semi-quantitative terms used for dosages, such as low | Glucocorticoid Therapy 903 Table 60-3 Terminology of Dosages of Glucocorticoids for Use in Rheumatology Low dose Medium dose High dose Very high dose Pulse therapy ≤7.5 mg prednisone or equivalent per day >7.5 mg, but ≤30 mg prednisone or equivalent per day >30 mg, but ≤100 mg prednisone or equivalent per day >100 mg prednisone or equivalent per day ≥250 mg prednisone or equivalent per day for 1 day or a few days or high. Based on pathophysiologic and pharmacokinetic data, standardization has been proposed to minimize problems in interpretation of these generally used terms (Table 60-3).2 Indications For each disease, indications for glucocorticoid therapy are discussed in the specific chapters. An overview is given here (Table 60-4), which summarizes only the general uses and dosages of glucocorticoids. Without detailed description, some of the indications could be considered questionable at first glance. In systemic sclerosis, glucocorticoids, especially in high doses, are contraindicated because of the risk of scleroderma renal crisis, but they may be useful for myositis or interstitial lung disease. Glucocorticoids are a basic part of the therapeutic strategy in myositis, polymyalgia rheumatica, and systemic vasculitis. For other diseases, glucocorticoids serve as adjunctive therapy or are not used at all. For instance in RA, glucocorticoids are almost exclusively used as adjunctive therapy in combination with other diseasemodifying antirheumatic drugs (DMARDs) (see later). In osteoarthritis, glucocorticoids are not given except for intraarticular injection if signs of synovitis of the osteoarthritic joint are present.41 For generalized soft tissue disorders, glucocorticoids are not indicated, and for localized soft tissue disorders, they should be used only for intralesional injection.42 Glucocorticoid Therapy in Rheumatoid Arthritis Glucocorticoids are a frequently applied medication in RA. In the past, more patients with RA seemed to be given concomitant glucocorticoids in the United States than in Europe—54% versus 27%43,44—whereas more recent data suggest that 38% of RA patients in the United States use glucocorticoids45 versus up to 55% of German RA patients.46 Aims of this therapy include reduction of signs and symptoms and inhibition of joint damage. Signs and Symptoms As can be seen in Table 60-4, RA is the only disease in which glucocorticoid therapy is often started and maintained at a low dose as additional therapy. The rationale for this therapy is a probable, relative insufficiency of the adrenal gland in patients with active RA.31 Glucocorticoids are highly effective for relieving symptoms in patients with active RA in doses of less than 10 mg/day. Many 904 PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS Table 60-4 General Use of Glucocorticoids in Rheumatology Initial Oral Dose* Low† Medium† High† Intravenous, Very High Dose† or Pulse 1 − − − − − − 2 2 1 − − 1 − 1 2 2 1 − − − − 1 1 − − − − − − − 1 2 1 1 2 2 1 − 2 Dermatomyositis, polymyositis Mixed connective tissue disease Polymyalgia rheumatica Sjögren’s syndrome, primary Systemic lupus erythematosus Systemic sclerosis − − − − − − − 1 3 − 2 1 3 − − 1 1 − 1 1 1 − 1 − − 1 − − − − Systemic Vasculitis in General − − 3 1 − Intra-articular Injection Arthritides Gout Juvenile idiopathic arthritis Osteoarthritis Pseudogout Psoriatic arthritis Reactive arthritis Rheumatic fever Rheumatoid arthritis Collagen Disorders *Initial dose is the dose at the start of therapy and often is decreased in time depending on disease activity. †Dose in prednisone equivalents per day: low, ≤7.5 mg; medium, >7.5 but ≤30 mg; high, >30 but ≤100 mg; very high, >100 mg. −, Rare use. 1, Infrequent use or use for therapy-resistant disease, complications, severe flare, and major exacerbation. 2, Frequently added to the basic therapeutic strategy. 3, Basic part of therapeutic strategy. patients become functionally dependent on this therapy, however, and continue it over the long term.47 A review of seven studies (253 patients) concluded that glucocorticoids, when administered for approximately 6 months, are effective for the treatment of RA.48 After 6 months of therapy, the beneficial effects of glucocorticoids seem to diminish. If this therapy then is tapered off and stopped, however, patients often—over some months—experience aggravation of symptoms. Radiologic Joint Damage: Glucocorticoids as DMARDs In 1995, joint-preserving effects of 7.5 mg of prednisolone daily for 2 years were described in patients with RA of short and intermediate duration who also were treated with DMARDs. The group of RA patients participating in this randomized, placebo-controlled trial was heterogeneous, not only with respect to disease duration, but also with respect to stages of the disease and types and dosages of DMARDs.49 In another trial published in 1997, patients with early RA were randomly assigned to step-down therapy with two DMARDs (sulfasalazine and methotrexate) and prednisolone (start 60 mg/day, tapered in six weekly steps to 7.5 mg/day and stopped at 34 weeks) or to sulfasalazine alone. In the combined drug strategy group, a statistically significant and clinically relevant effect in retarding joint damage was shown compared with the effect of sulfasalazine alone.50 In an extension of this study, long-term (4 to 5 years) beneficial benefits were shown regarding radiologic damage after the combination strategy.51 It has been hypothesized that the superior effect of the combination therapy in this trial can be ascribed to prednisolone because in three double-blind, randomized trials, the effect of the combination of methotrexate and sulfasalazine was not superior to that of either drug alone.52-54 In a German study, 200 patients with early RA were treated with methotrexate or intramuscular gold and were randomly assigned to additional treatment with 5 mg of prednisolone or placebo. After 2 years, progression of radiologic damage proved to be less in the prednisolone-treated patients than in those treated with placebo.55 In 2002, results of the Utrecht study on the effects of prednisolone in DMARD-naïve patients with early RA were published. This is the only placebo-controlled trial in which prednisolone was applied as monotherapy as the first step. The progression of radiologic joint damage was inhibited by 10 mg of prednisolone daily in these patients (who received DMARD therapy only as rescue).56 The Utrecht study reported a 40% decreased need for intra-articular glucocorticoid injections, a 49% decreased need for acetaminophen use, and a 55% decreased need for nonsteroidal anti-inflammatory drugs (NSAIDs) in the prednisolone group compared with the placebo group. This indicates that in clinical trials evaluating the clinical effects of DMARDs or glucocorticoids, additional therapies should be taken into account. In an extension of this study, at 3 years after the end of the study and 2 years after tapering off and stopping the prednisolone therapy, beneficial radiologic benefits of prednisolone were still present (Figure 60-7).57 In another 2-year study in 250 patients with early RA, 7.5 mg/day of prednisolone added to DMARD therapy retarded joint damage and increased the remission rate compared with placebo added to DMARDs.58 Even in an intensive treat-to-target methotrexate-based strategy in early RA, prednisone enhanced clinical efficiency and reduced erosive joint damage.58a CHAPTER 60 40 30 20 10 0 0 25 50 75 100 Figure 60-7 Cumulative probability plot of mean yearly radiographic progression over 3 years since the end of the original 2-year study in patients originally randomized to receive prednisone therapy (triangles) or placebo (circles).56,57 At the end of the 2-year trial, the prednisone therapy was tapered down and stopped, if possible. Y-axis, Yearly progression of radiographic joint damage according to the van der Heijde modification of the Sharp method. Negative studies on the effects of glucocorticoids on radiologic damage have also been published,59-61 but in early RA, evidence of glucocorticoid joint-sparing effects, which persist after therapy is stopped, seems convincing, thus classifying glucocorticoids as DMARDs. A meta-analysis on radiographic outcome analyzed 15 studies (two with negative results) that included a total of 1414 patients. Because different methods had been used in the individual trials, radiographic scores were expressed as a percentage of the maximum possible score for the specific radiographic method used. The standardized mean difference in progression was 0.40 in favor of strategies using glucocorticoids (95% confidence interval, 0.27 to 0.54). This was con sidered a conservative estimate because the most con servative estimate of the difference in each study had been chosen.62 It is still unknown, however, whether glucocorticoids can also inhibit progression of erosion in RA of longer duration than 2 years. A so-called window of opportunity may exist in the treatment of RA.63 If this window is present, effective treatment of early RA with glucocorticoids and DMARDs may result in an effect that lasts for a long time and in disease that is easier to control, whereas if effective treatment starts later, this opportunity may be lost, resulting in more difficult control of the disease with inflammation fueled by joint damage. Most studies on glucocorticoids and radiologic damage employed a dose of 5 to 10 mg/day of prednisone equivalent during 2 years, but a scheme starting with 60 mg/day tapered off and stopped within 34 weeks also was effective. In addition, because glucocorticoidinduced osteoporosis and peptic ulcer complications (if glucocorticoids are combined with nonsteroidal anti-inflammatory drugs [NSAIDs]) can be prevented much more effectively now than some decades ago, the jointprotective effect of prednisolone in RA during the first 2 | Glucocorticoid Therapy 905 years of the disease in a dose of 5 to 10 mg daily is a relevant finding. The joint-sparing effect of glucocorticoids probably is based on inhibition of proinflammatory cytokines such as IL-1 and TNF,64 which stimulate osteoblasts and T cells to produce receptor activator of nuclear factor κB (RANK) ligand. This binds to RANK on osteoclast precursor cells and on mature osteoblasts, leading to activation of osteoclasts, which are responsible for bone resorption, periarticular osteopenia, and formation of bone erosions in RA. A toxicity index score for DMARDs was published (based on symptoms, laboratory abnormalities, and hospitalization data) after evaluation of 3000 patients with more than 7300 patient-years from the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) database.65 Although this score has not been validated and is influenced by confounding-by-indication, it gives an impression of the relative toxicity of glucocorticoids. It is comparable with that of other immunosuppressive medications used in RA, such as methotrexate and azathioprine. A review also showed that the incidence, severity, and impact of adverse effects of low-dose glucocorticoid therapy in RA trials were modest and suggested that probably many of the well-known adverse effects of glucocorticoids are predominantly associated with high-dose treatment.66 Because many questions remain to be answered, such as how the effects of glucocorticoids compare with those of high dosages of methotrexate or of TNF blockers, and for how long glucocorticoids should be prescribed and in what dosages, the final place of glucocorticoid therapy in RA has to be clearly determined. Nevertheless in early RA the use of glucocorticoids generally has been accepted.66a Guidelines on how to use (low-dose) glucocorticoids and how to monitor this therapy have been developed.67,68 Prevention of Early (Rheumatoid) Arthritis Development with Glucocorticoids Recently, trials have been done to try to prevent arthralgia or early arthritis from progressing to chronic arthritis. In patients with (very) early arthritis or individuals with arthralgia and antibodies to citrullinated proteins or rheumatoid factor, intramuscular glucocorticoid injections did not prevent arthritis development in two placebo-controlled trials,69,70 but in another placebo-controlled double-blind trial these injections postponed the need for DMARDs and prevented 1 in 10 patients from progressing into RA at assessment at 12 months.71 These results are preliminary and nonconclusive, and it is clear that further resarch is needed. Chronobiology The rheumatoid inflammatory process and symptoms have a diurnal rhythm. Early in the morning, patients experience the most extensive joint stiffness and other symptoms and signs; this is due to the long rest period during the night that facilitates edema formation around inflamed joints and the circadian rhythm of cortisol (see Figure 60-6). In patients with RA with low or medium disease activity, serum cortisol maximum and minimum shift to earlier times of the day and night, whereas in patients with high 906 PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS disease activity, the circadian rhythm is markedly reduced or even lost. The timing of glucocorticoid administration may be important for efficacy and side effects. Older data in the literature on this topic are ambiguous.72,73 Recently, a trial was performed with a newly developed modified-release prednisone tablet that releases prednisone about 4 hours after ingestion. When it was taken in the evening, thus adapting its release to circadian increases in proinflammatory cytokine concentrations, symptoms of RA early in the morning were lessened compared with those reported when the same dose of prednisone was taken early in the morning. This 3-month double-blind trial included RA patients with a duration of morning stiffness of 45 minutes or longer, a pain score of 30 mm or less on a 100-mm visual analog scale, three or more painful joints, one or more swollen joints, and an erythrocyte sedimentation rate (ESR) of 28 mm or greater or a C-reactive protein concentration 1.5 times or more the upper limit of normal, who were on glucocorticoids at least 3 months with a stable daily dose of 2 to 10 mg prednisone equivalent for at least 1 month. Patients were randomized to continue their prednisone or to switch to modified-release prednisone in a double-dummy way. At the end of the trial, the difference in duration of morning stiffness was about 30 minutes, in favor of the modified-release prednisone group. However, no differences were noted in all other variables of disease activity between the two groups. The safety profile did not differ between treatments.74 Longer-term benefits and risks of this preparation and application in other inflammatory rheumatic diseases have yet to be investigated.75 Other Developments to Improve the Therapeutic Ratio of Glucocorticoids In addition to guidelines put forth to improve the clinical use of existing glucocorticoids,67,68 other formulations have been and are being developed. Deflazacort,76 an oxazoline derivative of prednisolone introduced in 1969, was initially thought to be as effective as prednisone while inducing fewer adverse events, but there was the issue of the real equivalence ratio compared with prednisone77; this drug has not represented a major breakthrough. Knowledge about the mechanisms of glucocorticoids (transrepression and transactivation leading, respectively, to predominantly beneficial effects and adverse effects; see earlier) led to the development of selective glucocorticoid receptor agonists or dissociating glucocorticoids,78 but as yet they have not entered the market. Glucocorticoid preparations releasing nitric oxide, the so-called nitrosteroids, could induce stronger anti-inflammatory effects because nitric oxide has antiinflammatory effects too.79 These drugs have to be tested in patients yet. The drug combination prednisolone and dipyridamole has been reported to boost and extend the net glucocorticoid effect in laboratory models.80 The next required step will be to demonstrate the improved therapeutic ratio in patients in adequate comparative clinical trials by assessing predefined beneficial effects and adverse effects in a standardized way.81 Liposomes containing glucocorticoids and targeted to integrins expressed on endothelial cells at sites of inflammation have been studied; these deliver their glucocorticoids specifically at sites of inflammation.82 Their selective biodistribution might allow for less frequent and lower dosing, which could result in an improved therapeutic ratio. The safety of liposomal prednisolone has been evaluated in a small group of RA patients, and the results (up until now published only as an abstract) seem promising.83All of these new applications have to be tested further before they can be used in daily clinical practice. Alternate-Day Regimens For oral, long-term use of glucocorticoid therapy, alternateday regimens have been devised in an attempt to alleviate the undesirable side effects, such as hypothalamic-pituitaryadrenal axis suppression. Alternate-day therapy uses a single dose administered every other morning, which is usually equivalent to, or higher than, twice the usual or preestablished daily dose. The rationale for this regimen is that the body, including the hypothalamic-pituitary-adrenal axis, is exposed to exogenous glucocorticoid only on alternate days. This rationale makes sense only for usage of a class and dosage of a glucocorticoid that suppresses the hypothalamic-pituitary-adrenal axis activity for less than 36 hours after a single dose. Another prerequisite is that the patient should have a responsive hypothalamic-pituitaryadrenal axis that is not chronically suppressed by previous glucocorticoid regimens. The alternate-day schedule does not work in patients on long-term medium- or high-dose glucocorticoids suppressing hypothalamic-pituitary-adrenal axis activity for longer than 36 hours. Alternate-day therapy is unsuccessful in most patients who require glucocorticoids. Patients with RA often experience exacerbation of symptoms on the second day. This experience is in line with the clinical impression that a single dose of glucocorticoids daily is less effective in RA than half that dose, given twice daily. In giant cell arteritis, alternate-day glucocorticoid therapy also is less effective than daily administration.84,85 Generally, alternate-day regimens are used rarely in rheumatology today, except in patients with juvenile idiopathic arthritis, in whom alternate-day glucocorticoid usage results in less inhibition of body growth than is associated with daily usage.86 If treatment has been initiated with daily administration, the change to alternate-day therapy preferably should be made after the disease has stabilized. Glucocorticoid Sensitivity and Resistance A small proportion of patients does not react favorably to glucocorticoids or even fails to respond to high doses. Also, susceptibility to adverse effects of glucocorticoids varies widely. Several different factors are involved in the variability of glucocorticoid sensitivity in patients with rheumatic diseases, and an understanding of the mechanisms involved might eventually allow their modulation. Potential mechanisms of glucocorticoid resistance in inflammatory diseases have been reviewed extensively.87 Hereditary glucocorticoid resistance (rare) and increased susceptibility to glucocorticoids have been related to specific polymorphisms of the glucocorticoid receptor gene. The glucocorticoid receptor exists as α and β isoforms, but only the α isoform binds glucocorticoids. The β isoform CHAPTER 60 | Glucocorticoid Therapy 907 Table 60-5 Glucocorticoid Tapering Scheme to Hand Out to Patients* Period 1 Period 2 Period 3 Period 4 Period 5 Period 6 Period 7 Monday Tuesday Wednesday Thursday Friday Saturday Sunday High High High Low Low Low Low High Low Low High High Low Low High High High Low Low Low Low High High Low High Low High Low Low High High Low Low Low Low High Low Low High High Low Low High High High Low Low Low Low *At each consecutive period (e.g., 1 week or some weeks), the number of days during which a low dose should be taken increases by 1. After completion of period 7, the next step in tapering can be taken; the dose called “low” during the previous 7 periods now is “high,” and so on. In case of aggravation of symptoms, the patient should not diminish the dose and should contact the specialist. functions as an endogenous inhibitor of glucocorticoids and is expressed in several tissues. Glucocorticoid resistance has been associated with enhanced expression of this β receptor, but this is unlikely to be an important mechanism for glucocorticoid resistance because in most cells, apart from neutrophilic granulocytes, expression of the β receptor is much less than that of the α receptor.87 The protein lipocortin-1 (or annexin-1) inhibits eicosanoid synthesis. Glucocorticoids are thought to stimulate lipocortin-1. In patients with RA, autoantibodies to lipocortin-1 have been described. The titers in these patients correlate with the height of maintenance doses of glucocorticoids, suggesting that these antibodies may lead to glucocorticoid resistance. Although glucocorticoids exert most of their immunosuppressive actions through inhibition of cytokine production, high concentrations of cytokines, especially IL-2, antagonize the suppressive effects of glucocorticoids in a dose-dependent manner.77 The balance is usually in favor of glucocorticoids, but high local concentrations of cytokines may result in localized glucocorticoid resistance that cannot be overridden by exogenous glucocorticoids. Also, the macrophage migration inhibitory factor may play a role in steroid resistance in RA. This proinflammatory cytokine is involved in TNF synthesis and T cell activation, suggesting a role in the pathogenesis of RA. Macrophage migration inhibitory factor is suppressed by higher concentrations of glucocorticoids, but it is induced by low concentrations, leading to stimulation of inflammation.78 Other possible mechanisms of glucocorticoid resistance include activation of mitogen-activated protein kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein-1, reduced histone deacetylase-2 expression, and increased P-glycoprotein–mediated drug efflux.87 Also, drugs may play a role in glucocorticoid sensitivity and resistance (see also the section on drug interactions). Sulfasalazine increases the sensitivity of immune cells for glucocorticoids and thus might be a future option for preventing or treating glucocorticoid resistance.13 Mifepristone is an antiprogesterone drug and glucocorticoid receptor antagonist; chlorpromazine inhibits glucocorticoid receptor– mediated gene transcription.88 Glucocorticoid Withdrawal Regimens Because of potential side effects, glucocorticoids usually are tapered off as soon as the disease being treated is under control. Tapering must be done carefully to avoid recurrent activity of the disease and, infrequently, cortisol deficiency resulting from chronic hypothalamic-pituitary-adrenal axis suppression. Gradual tapering permits recovery of adrenal function. There is no best scheme based on controlled, comparative studies for tapering glucocorticoids. Tapering depends on the individual disease, the disease activity, doses and duration of therapy, and clinical response, which also depends on each individual’s glucocorticoid sensitivity. Only generic guidelines can be offered. To taper the dose of prednisone, decrements of 5 to 10 mg every 1 to 2 weeks can be used when the prednisone dose is more than 40 mg/ day, followed by 5-mg decrements every 1 to 2 weeks at a dose between 40 and 20 mg/day, and finally 1 to 2.5 mg/day decrements every 2 to 3 weeks at a prednisone dose of less than 20 mg/day. Another scheme is to taper 5 to 10 mg every 1 to 2 weeks down to 30 mg/day of prednisone, and when the dose is less than 20 mg/day, to taper 2.5 to 5 mg every 2 to 4 weeks down to 10 mg/day; thereafter, the dose is tapered 1 mg each month or 2.5 mg (half a 5-mg tablet of prednisolone) each 7 weeks. For tapering every 7 weeks or over longer periods, a printed schedule can be given to the patient, such as the one shown in Table 60-5. Adaptations of Glucocorticoid Doses, Stress Regimens, and Perioperative Care Patients on long-term low-dose glucocorticoid medication have suppressed adrenal activity and should be advised to double their daily glucocorticoid dose or to increase the dose to 15 mg prednisolone or equivalent if they develop fever attributed to infection, and to seek medical help. In case of major surgery, given the unreliable prediction of adrenal suppression on the basis of duration and dose of glucocorticoid therapy (see the section on effects of glucocorticoids on the hypothalamic-pituitary-adrenal axis), many physicians recommend “stress doses” of glucocorticoids for patients with low risk of adrenal suppression. The scheme of 100 mg of hydrocortisone intravenously just before surgery, followed by an additional 100 mg every 6 hours for 3 days, is based on anecdotal information and is not always necessary.89,90 A scheme with a lower dose, possibly reducing the risk of postoperative bacterial infectious complications, is to infuse continuously 100 mg of hydrocortisone intravenously on the day of surgery, followed by 25 to 50 mg of hydrocortisone every 8 hours for 2 or 3 days. Another option is to administer the usual dose of oral glucocorticoid orally or (the equivalent) parenterally on the day of surgery, followed by 25 to 50 mg of hydrocortisone every 8 hours for 2 or 3 days. In cases of minor surgery, it is probably sufficient to double the oral dose or to increase the dose to 15 mg of 908 PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS prednisolone or equivalent for 1 to 3 days. No comparative randomized studies on different perioperative glucocorticoid stress schemes have been published, however. Because in glucocorticoid-induced secondary adrenal insufficiency, aldosterone secretion is preserved, mineralocorticoid therapy is unnecessary, in contrast to in primary adrenal insufficiency. Glucocorticoid-Sparing Agents For most inflammatory rheumatic diseases, including SLE, vasculitis, RA, and myositis, other immunomodulatory drugs are often added to therapy with glucocorticoids, such as azathioprine and methotrexate, and especially in case of systemic vasculitis, cyclophosphamide. For these indications, biologic agents are increasingly used.91 An exception is polymyalgia rheumatica, which is managed primarily with glucocorticoids alone. Combination therapy is applied early in the disease when the disease is one for which it is known that the effect of the combination is better than that of glucocorticoids alone (e.g., in the case of systemic vasculitis), or if the disease (e.g., inflammatory myositis) seems resistant to high initial doses of glucocorticoids. If at a later stage of the disease, immunomodulatory drugs are added to therapy with glucocorticoids to enable further reduction of the dose to decrease the risk of side effects, these immunomodulatory drugs are termed glucocorticoidsparing agents. For this purpose, azathioprine and methotrexate are often used, although any drug that has an additive or synergistic effect in suppressing the disease, enabling reduction of the glucocorticoid dose, could be used as a glucocorticoid-sparing agent. Glucocorticoid Pulse Therapy Glucocorticoid pulse therapy is used in rheumatology, especially for remission induction or treatment of flares of inflammatory rheumatic disorders and vasculitides (see Table 60-4). In RA, pulse therapy is applied to treat serious complications of the disease and to induce remission in active disease, often during the initiation phase of a (new) DMARD strategy. In the latter patients, pulse therapy with schemes of 1000 mg of methylprednisolone given intravenously has been proven effective in many studies. The beneficial effect generally lasts about 6 weeks, with large variation in the duration of the effect.92 It does not seem sensible to apply pulse therapy in active RA, unless a change in the therapeutic strategy (i.e., in second-line antirheumatic treatment) aims to stabilize over the long term any remission induced by the pulse therapy. Short-term effects of pulse therapy in patients with established, active RA at various dimensions of health status closely resemble the long-term effects of effective conventional DMARD therapy, such as methotrexate, in patients with early RA.93 In 144 patients with biopsy-confirmed giant cell arteritis, of whom 91 were seen initially with visual loss and 53 without visual loss, no evidence was found that intravenous glucocorticoid pulse therapy (usually 150 mg dexamethasone sodium phosphate every 8 hours for 1 to 3 days) was more effective than high daily doses (80 to 120 mg) of oral prednisone in preventing visual deterioration.94 The risk of adverse effects of pulse therapy is not the same for all rheumatic disorders. In patients with SLE, osteonecrosis and psychosis seem to be more frequent side effects of pulse therapy compared with those seen in patients with RA.93 Osteonecrosis and psychosis also can be complications of SLE itself, however. Contraindications for pulse therapy include pregnancy and lactation, infection, current peptic ulcer disease, glaucoma, badly controlled hypertension, and diabetes mellitus. In cases with a family history of glaucoma or well-controlled hypertension or diabetes mellitus, pulse therapy can be applied with checks, respectively, of eye and blood pressure and of blood glucose values. Intralesional and Intra-articular Glucocorticoid Injections Injections with glucocorticoids are widely used for arthritis (see Table 60-4), tenosynovitis, bursitis, enthesitis, and compression neuropathies such as carpal tunnel syndrome.42 Generally, the effect occurs within days; it can be longlasting, but if the underlying disease is active, the effect is of short duration. Administration of a local anesthetic concurrently with intra-articular or soft tissue injection of a glucocorticoid may provide immediate pain relief. Soluble glucocorticoids (e.g., phosphate salts) have a more rapid onset of action with probably less risk of subcutaneous tissue atrophy and depigmentation of the skin when given intralesionally. Insoluble glucocorticoids are longer acting and might further decrease the soft tissue fibrous matrix, so they should be used with caution in places with thin skin, especially in elderly patients and in those with peripheral vascular disease. Insoluble glucocorticoids are more safely given into deep sites. Short-acting soluble glucocorticoids can be mixed with long-acting insoluble glucocorticoids to combine rapid onset with longacting effect. The effect of intra-articular glucocorticoid injection probably depends on several factors: the underlying disease (e.g., RA, osteoarthritis), the treated joint (size, weight bearing, or non–weight bearing), the activity of arthritis, the volume of synovial fluid in the joint to be treated,46 the application of arthrocentesis (synovial fluid aspiration) before injection, the choice and dose of the glucocorticoid preparation, application of rest to the injected joint, and the injection technique used. The effects of injections seem to be less favorable in osteoarthritis than in RA.95 Arthrocentesis before injection of the glucocorticoid preparation reduces the risk for relapse of arthritis. Triamcinolone hexacetonide, which, among the injectable glucocorticoids, is the least soluble preparation, shows the longest effect. Theoretically, rest of the injected joint minimizes leakage of the injected glucocorticoid preparation into the systemic circulation (via the hyperemic, inflamed synovium by enhanced pressure in the joint during activity), minimizes the risk of cartilage damage, and enhances repair of inflammatory tissue damage. Advice and procedures for the postinjection period in terms of activity vary from no restrictions, to minimal activity of the injected joint for a couple of days, to bed rest for 24 hours after injection of a knee joint or splinting of injected joints. Based on the literature, no definite evidence-based recommendations can be made, but it CHAPTER 60 seems prudent to rest and to not overuse the injected joint for several days, even if pain is relieved. It is recommended that intra-articular glucocorticoid injections be repeated no more often than once every 3 weeks, and that they be given no more frequently than three times a year in a weight-bearing joint (e.g., the knee) to minimize glucocorticoid-induced joint damage. This recommendation seems sensible, but no definitive clinical evidence is available to support it. As one would expect, accuracy of steroid placement influences the clinical outcome of glucocorticoid injections into the shoulder and probably into other joints as well.96 This is important because it is estimated that a few more than half of shoulder injections are inaccurately placed.96,97 The reported infection rate of joints after local injection with glucocorticoids is low, ranging from 1 case in 13,900 to 1 in 77,300 injections.98,99 Introduction of disposable needles and syringes has helped reduce the risk. In a 3-year prospective study in an urban area of 1 million people in the Netherlands, bacterial infections were detected in 214 joints (including 58 joints with a prosthesis or osteosynthetic material) of 186 patients; only 3 of these joint infections were attributed to an intra-articular injection.100 Other adverse effects of local glucocorticoid injections include systemic adverse effects of the glucocorticoid, such as disturbance in the menstrual pattern, hot flush–like symptoms the day of or the day after injection, and hyperglycemia in diabetes mellitus.42 Local complications include subcutaneous fat tissue atrophy (especially after improper local injection), local depigmentation of the skin, tendon slip and rupture, and lesions to local nerves.42 Therapeutic effects Glucocorticoid Therapy System Adverse Effect Skeletal Gastrointestinal Osteoporosis, osteonecrosis, myopathy Peptic ulcer disease (in combination with nonsteroidal anti-inflammatory drugs), fatty liver Predisposition to infection, suppressed delayed hypersensitivity (Mantoux test) Fluid retention, hypertension, accelerated arteriosclerosis, arrhythmias Glaucoma, cataract Skin atrophy, striae, ecchymoses, impaired wound healing, acne, buffalo hump, hirsutism Cushingoid appearance, diabetes mellitus, changes in lipid metabolism, enhanced appetite and weight gain, electrolyte abnormalities, hypothalamic-pituitaryadrenal axis suppression, suppression of gonadal hormones Insomnia, psychosis, emotional instability, cognitive effects Immunologic Cardiovascular Ocular Cutaneous Endocrine Behavioral ADVERSE EFFECTS AND MONITORING Given the diversity of their mechanisms and sites of action, it is not surprising that glucocorticoids can cause a wide array of adverse effects (Table 60-6 and Figure 60-8). Most of these adverse effects cannot be avoided. However, the risk of most complications is dosage and time dependent; minimizing the quantity of glucocorticoid minimizes the risk of complications.68 Dose-related patterns of adverse DMARD effect in RA Pain ↓ Swelling ↓ Stiffness ↓ Physical disability ↓ Vasculitis, serositis ↓ Endothelial dysfunction ↓ Effect on cells, tissue, and organs: clinical effects Vessel GC treatment Infections Bone Osteonecrosis Osteoporosis Eyes CNS HPA-axis Skin Metabolism Permeability ↓ Cardiovascular Muscle Myopathy 909 Table 60-6 Adverse Effects of Glucocorticoids Anti-inflammatory Immunosuppressant Anti-allergic | Increased CV risk Cataract Glaucoma Stomach Hirsutism Skin thinning Weight gain/obesity Fluid retention/edema Gastric ulcer Cushing syndrome (if concomitant Impaired glucose metabolism: NSAIDs) • insulin resistance • beta cell dysfunction Neuropsychiatric symptoms HPA insufficiency Adverse effects Figure 60-8 The spectrum of glucocorticoid (GC) therapy: beneficial effects in the upper green part of the figure, adverse effects in the lower red part. CNS, central nervous system; CV, cardiovascular; DMARD, disease-modifying antirheumatic drug; HPA, hypothalamic-pituitary-adrenal; NSAIDs, nonsteroidal anti-inflammatory drugs; RA, rheumatoid arthritis. (Adapted from Buttgereit F, Burmester GR, Lipworth BJ: Optimised glucocorticoids therapy: the sharpening of an old spear, Lancet 365:801–803, 2005.) 910 PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS Inflammatory disease activity: proinflammatory mediators D supplementation and prescribing a bisphosphonate on indication. Osteonecrosis Glucocorticoid therapy Negative effects • Bone mass • Lipids, endothelium • Glucose metabolism • Infection risk Figure 60-9 The interplay of glucocorticoid therapy, the inflammatory disease, and adverse effects, which, in combination with bias by indication, makes it hard in not randomized trials or cohorts to discriminate the negative effects of glucocorticoids from negative effects of the disease itself. effects of glucocorticoids have been described.101 Low-dose glucocorticoid therapy is safer than is commonly thought,66 and medium- to long-term glucocorticoid therapy in RA is associated with limited toxicity compared with use of placebo,102 but sensitivity for adverse effects differs among individuals. It is a clinical observation that some patients develop adverse effects after small doses of glucocorticoids, whereas other patients receive high doses without serious adverse effects. Apparent individual susceptibility to adverse effects does not seem to always parallel individual susceptibility to beneficial effects. Osteoporosis, diabetes, and cardiovascular disease are ranked by both patients and rheumatologists among the most worrisome adverse effects of glucocorticoids.103 However, the frequency and the severity of glucocorticoid-related adverse effects have seldom been studied systematically. A problem for nonrandomized studies looking at glucocorticoid-related adverse effects is bias by indication: patients with severe disease tend to take glucocorticoids more frequently than those with less severe disease, and the disease as well as the glucocorticoids can cause unfavorable signs and symptoms104; on the other hand, glucocorticoids decrease disease activity and therewith influence the frequency and severity of disease-associated signs and symptoms (Figure 60-9). Skeletal Adverse Effects Osteoporosis Osteoporosis is a well-known adverse effect of glucocorticoids that can be prevented to a large degree. International and national guidelines to minimize the occurrence of glucocorticoid-induced osteoporosis have been developed and are updated periodically.105,106 Preventive and therapeutic management of glucocorticoid-induced osteoporosis is discussed in detail in Chapter 99. In short, following the actual guideline consists of providing calcium and vitamin High-dose glucocorticoids given over longer periods are implicated as a cause of osteonecrosis, especially in children and patients with SLE. Vascular mechanisms seem to be involved. Ischemia possibly may be caused by microscopic fat emboli or impingement of the sinusoidal vascular bed by increased intraosseous pressure caused by fat accumulation. An early symptom is diffuse pain, which becomes persistent and increases with activity. Most frequently, hip or knee joints are involved; ankle and shoulder joints are involved less frequently. For early assessment, magnetic resonance imaging is the most sensitive investigative tool. Radionuclide bone scans provide less specific information. Plain radiographs are adequate only for follow-up. Treatment in the early stage includes immobilization and decreased weight bearing. Surgical decompression, joint replacement, or both follow this if needed. No preventive measures are known; awareness is the most important factor in early detection. Myopathy Weakness in proximal muscles, especially of the lower extremities, occurring within weeks to months after initiation of treatment with glucocorticoids, or after an increase in the dosage, may indicate steroid myopathy. It is often suspected but is infrequently found; it occurs almost exclusively in patients treated with high dosages (>30 mg/day prednisone or equivalent). Diagnosis is clinical and can be confirmed by a muscle biopsy specimen that reveals atrophy of type II fibers and lack of inflammation; no elevation of serum muscle enzymes is noted. Treatment consists of withdrawal of the glucocorticoid; if this is possible, a prompt decrease in symptoms may ensue. A rare syndrome of rapidonset, acute myopathy, occurring within days after the start of high-dose glucocorticoids or pulse therapy, has been described; muscle biopsy specimens show atrophy and necrosis of muscle fibers. Gastrointestinal Adverse Effects Peptic Ulcer Disease Data from the literature on upper gastrointestinal safety of oral glucocorticoids are inconclusive. The fact that glucocorticoids inhibit the production of COX-2 without hampering the production of COX-1 supports studies that found no increased risk. In other studies, a relative risk of serious upper gastrointestinal peptic complications of about 2 was found.107 When glucocorticoids are used in combination with NSAIDs, the relative risk of peptic ulcer disease and associated complications is about 4.108 Therefore in cases of co-medication with NSAIDs, consider co-treatment with a proton pump inhibitor, or prescribe a COX-1sparing NSAID.66 In patients treated with glucocorticoids without concomitant use of NSAIDs, no indication for gastrointestinal protective agents exists, unless other risk factors for peptic complications are present. CHAPTER 60 Other Gastrointestinal Adverse Effects Although glucocorticoids usually are listed as one of the many potential causes of pancreatitis, evidence for such an association is weak and is difficult to separate from the underlying disease, such as vasculitis or SLE.109 Asymptomatic and symptomatic colonization of the upper gastrointestinal tract with Candida albicans is increased in patients treated with glucocorticoids, especially when other risk factors are present, such as advanced age, diabetes mellitus, and concomitant use of other immunosuppressive agents. Glucocorticoids may mask symptoms and signs usually associated with the occurrence of intra-abdominal complications, such as perforation of the intestine and peritonitis (e.g., as a complication of diverticulitis), and can lead to a delay in diagnosis with increased morbidity and mortality. Immunologic Adverse Effects At high doses, glucocorticoids diminish neutrophil phagocytosis and bacterial killing in vitro, whereas in vivo, normal bactericidal and phagocytic activities are found. Monocytes are more susceptible; during treatment with medium to high doses of glucocorticoids, bactericidal and fungicidal activity in vivo and in vitro is reduced. These factors may influence the risk of infection. From epidemiologic studies, treatment with a daily dose of less than 10 mg of prednisone or equivalent seems to lead to no or an only slightly increased risk of infection; however, if doses of 20 to 40 mg daily are used, the risk of infection is increased (relative risk of 1.3 to 3.6).110 This risk increases with increased dose and duration of treatment.45 In a meta-analysis of 71 trials involving more than 2000 patients with different diseases and different doses of glucocorticoids, an increased relative risk of infection of 2 was found. The risk varied according to the type of disease being treated. Five of these trials involved patients with rheumatic diseases and showed no increased risk (relative risk of 1).110 The same was found in a double-blind, placebocontrolled, 2-year trial in patients with early RA, in which the effect of 10 mg of prednisone daily was compared with that of placebo.56 In one study, after adjustments were made for covariates, prednisone use dose dependently increased the risk of hospitalization for pneumonia.45 In patients treated with glucocorticoids, especially at high doses, clinicians should anticipate infections with usual and unusual organisms, realizing that glucocorticoids may blunt classic clinical features, thus delaying diagnosis. Cardiovascular Adverse Effects Mineralocorticoid Effects Some glucocorticoids have mineralocorticoid actions (see Table 60-1), including reduced renal excretion of sodium and chloride and increased excretion of potassium, calcium, and phosphate. This activity may lead to edema, weight gain, increased blood pressure, and heart failure (caused by reduced excretion of sodium and chloride); cardiac arrhythmia (resulting from increased excretion of potassium); or tetany and electrocardiographic changes (related to hypocalcemia). | Glucocorticoid Therapy 911 Low doses of glucocorticoid are not a cause of hypertension, in contrast to higher doses.111 No formal studies addressing the effects of glucocorticoids in previously hypertensive patients have been reported. Two randomized, controlled studies in patients with myocarditis and idiopathic cardiomyopathy showed no differences between placebo-treated or glucocorticoid-treated groups after 1 year or in survival at 2 and 4 years.112,113 Atherosclerosis Accelerated atherosclerosis and elevated cardiovascular risk have been reported in patients with SLE and in patients with RA.114 Glucocorticoids may enhance cardiovascular risk via their potentially deleterious effects on lipids,115 glucose tolerance, insulin production and resistance, blood pressure, and obesity.114 However, these conditions seem not to be adverse effects of low-dose glucocorticoids. Furthermore, atherosclerosis itself has been recognized as an inflammatory disease of arterial walls, for which glucocorticoids may be beneficial; glucocorticoids have been found to inhibit macrophage accumulation in injured arterial walls in vitro, possibly resulting in attenuation of the local inflammatory response.116 Low-dose glucocorticoids might also improve dyslipidemia associated with inflammatory disease.114,117-119 However, the effects on lipids and other cardiovascular risk factors of low-dose glucocorticoids in inflammatory diseases probably are different from those of medium and high doses of glucocorticoids,115 or those of glucocorticoid therapy in noninflammatory diseases. This, along with the interplay of disease activity, glucocorticoids, and adverse effects (see Figure 60-9), makes it difficult to judge the net adverse effects of glucocorticoids on cardiovascular risk and lipids.120 The finding that a common haplotype of the glucocorticoid receptor gene is associated with heart failure, and that this association is mediated in part by low-grade inflammation, complicates this issue even further.121 Ocular Adverse Effects Cataract Glucocorticoids tend to stimulate the formation of posterior subcapsular cataract especially,122 but the risk of cortical cataract also seems increased, with an odds ratio of 2.6.123 To some extent, the likelihood or severity of this adverse effect depends on dose and duration of treatment. In patients treated long term with glucocorticoids at a dosage of 15 mg or more of prednisone daily for 1 year, cataract is observed frequently; in patients receiving long-term therapy with less than 10 mg of prednisone daily, the percentage of cataract is less, but cataract may develop at dosages greater than 5 mg/day of prednisone equivalent.46 These cataracts are usually bilateral but progress slowly. They may cause glare disturbance but usually cause little visual impairment, except at end stages. Glaucoma By increasing intraocular pressure, glucocorticoids may cause or aggravate glaucoma. Patients with a family history 912 PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS of open-angle glaucoma and patients with high myopia are probably prone to develop this adverse effect, especially when receiving high doses of glucocorticoids; checks of intraocular pressure are then warranted. If increased, patients need to be treated with medications that reduce intraocular pressure, often for a prolonged period after stopping the glucocorticoid.124 Topical application of a glucocorticoid in the eye has a more pronounced effect on intraocular pressure compared with systemic glucocorticoid therapy.125 Dermal Adverse Effects Clinically relevant adverse effects of glucocorticoids on skin include cushingoid appearance, easy bruising, ecchymoses, skin atrophy, striae, disturbed wound healing, acne, perioral dermatitis, hyperpigmentation, facial redness, mild hirsutism, and thinning of scalp hair. The physician often considers these changes to be of minor clinical importance, but they may be disturbing to the patient.103 No reliable data on the exact frequency of these adverse effects are available, but these adverse effects are dependent on duration of therapy and dose.46 Many physicians recognize immediately the skin of a patient who has been taking glucocorticoids on a long-term basis. Endocrine Adverse Effects Glucose Intolerance and Diabetes Mellitus Glucocorticoids increase hepatic glucose production and induce insulin resistance by inhibiting insulin-stimulated glucose uptake and metabolism by peripheral tissues. Glucocorticoids probably also have a direct effect on beta cells of the pancreas, resulting in enhanced insulin secretion during glucocorticoid therapy. It may take only a few weeks before glucocorticoid-induced hyperglycemia occurs with low and medium glucocorticoid doses. One case-control, population-based study in previously nondiabetic subjects suggested an odds ratio of 1.8 for the need to initiate antihyperglycemic drugs during glucocorticoid therapy with doses of 10 mg or less of prednisone or equivalent per day. This risk increased with higher daily doses of glucocorticoids. The odds ratio was 3 for 10 to 20 mg, 5.8 for 20 to 30 mg, and 10.3 for 30 mg or more of prednisone or equivalent per day.126 It is likely that risk is increased further in patients with other risk factors for diabetes mellitus, such as a family history of the disease, advanced age, obesity, and previous gestational diabetes. Postprandial hyperglycemia and only mildly elevated fasting glucose concentrations are characteristic of glucocorticoid-induced diabetes mellitus. Worsening of glycemic control can be expected in patients with established glucose intolerance or diabetes mellitus. Usually, glucocorticoid-induced diabetes is reversible when the drug is discontinued, unless clear glucose intolerance was pre-existent. Fat Redistribution and Body Weight One of the most notable effects of long-term endogenous or exogenous glucocorticoid excess is the redistribution of body fat. Centripetal fat accumulation with thin extremities is a characteristic feature of patients exposed to long-term high-dose glucocorticoids. Potential mechanisms include increased conversion of cortisone to cortisol in visceral adipocytes, hyperinsulinemia, and changes in expression and activity of adipocyte-derived hormones and cytokines, such as leptin and TNF.127 Protein loss resulting in muscle atrophy also contributes to the change in body appearance. Increased appetite influences body weight during glucocorticoid therapy, but patients with active inflammatory disease tend to lose weight, which can be prevented with disease control by drugs, including glucocorticoids. Trials in patients with RA given low-dose glucocorticoids for a prolonged period showed only minor effects on fat redistribution and body weight.55,56 Dyslipidemia See the earlier section, “Atheroslerosis.” Suppression of the Hypothalamic-Pituitary-Adrenal Axis In the section on effects of glucocorticoids on the hypothalamic-pituitary-adrenal axis, mechanisms of chronic suppression of the hypothalamic-pituitary-adrenal axis by administration of exogenous glucocorticoids are described. In such a situation, acute discontinuation of glucocorticoid therapy may lead to acute adrenal insufficiency with possible circulatory collapse and death.11,128 About 10 years after glucocorticoid therapy became available, the first well-documented case of adrenal insufficiency after withdrawal of exogenous glucocorticoid was reported.129 Acute cessation of glucocorticoid therapy without tapering is indicated for corneal ulceration by herpes virus, which can lead rapidly to perforation of the cornea, and glucocorticoid-induced acute psychosis. In these patients, assessment of adrenal responsiveness on a corticotropin test seems prudent. Not all patients with a blunted cortisol response have signs or symptoms of adrenal insufficiency, however. Clinical signs and symptoms of chronic adrenal hypofunctioning are nonspecific and include fatigue and weakness, lethargy, orthostatic hypotension, nausea, loss of appetite, vomiting, diarrhea, arthralgia, and myalgia. These symptoms partially overlap glucocorticoid withdrawal symptoms, such as fatigue, arthralgia, and myalgia. When in doubt, measurements of serum cortisol levels and the corticotropin stimulation test are indicated. Glucocorticoid withdrawal symptoms are sometimes difficult to discriminate from symptoms of the primary disease, such as polymyalgia rheumatica. Because mineralocorticoid secretion remains intact via the renin-angiotensin-aldosterone axis, serious electrolyte disturbances are uncommon. Adverse Behavioral Effects Glucocorticoid treatment is associated with a variety of behavioral symptoms. Although most attention has been directed toward specific dramatic disturbances collectively described under the term glucocorticoid psychosis, less florid effects also occur that may cause distress to a patient and CHAPTER 60 warrant medical attention.103 Minor behavioral manifestations may also occur on withdrawal of glucocorticoids. Steroid Psychosis Overt psychosis is rare and usually is associated with highdose glucocorticoids or glucocorticoid pulse therapy, but psychosis may also be a complication of the disease itself, especially SLE. This makes it difficult to distinguish in an individual SLE patient with psychosis whether the condition is a complication of the disease, of the therapy, or of both. Isolated psychosis is seen in about 10% of glucocorticoidrelated cases, and in most patients, affective disorders are present as well. Around 40% of cases of glucocorticoidinduced psychosis manifest as depression, whereas mania, often dominated by irritability, is predominant in 30% of cases.130 Psychotic symptoms usually start just after initiation of treatment (60% within the first 2 weeks, 90% within the first 6 weeks), and remission after drug dose reduction or withdrawal follows the same pattern. Although the data are largely anecdotal, individuals developing steroid psychosis frequently have had prior evidence of some dissociative symptoms. Occasionally, remission occurs without dose reduction. Minor Mood Disturbances Glucocorticoids have been associated with a wide variety of low-grade disturbances, such as depressed or elated mood (euphoria), insomnia, irritability, emotional instability, anxiety, memory failure, and other cognition impairments. Although the symptoms may not become severe enough for a specific diagnosis, they warrant attention—not only because they cause distress to the patient, but also because they may interfere with evaluation and treatment of the underlying disease. Most physicians recognize the occurrence of such symptoms in many glucocorticoid-treated patients; these symptoms may occur in varying degrees in up to 50% of treated patients within the first week. The exact incidence in rheumatic patients exposed to the usual doses of glucocorticoids is unknown; most series dedicated to mood disturbances studied high doses.131 It is important to inform patients about these minor mood disturbances before starting glucocorticoid therapy.103 Monitoring Glucocorticoid-related adverse effects have seldom been studied systematically. Mostly based on expert and patient opinion, recommendations have been formulated for monitoring low-dose glucocorticoid therapy. The conclusion is that in daily practice, standard care monitoring for serious diseases warranting glucocorticoid therapy need not be extended for patients on low-dose glucocorticoid therapy, except for monitoring for osteoporosis (follow national guidelines) and baseline assessments of fasting blood glucose and of risk factors for glaucoma, as well as a baseline check for ankle edema.67 Of course, for medium and high dosages, monitoring should be extended, not only to monitor for adverse effects of glucocorticoid therapy, but also to check for adverse effects of the concomitant medication and | Glucocorticoid Therapy 913 complications of the severe disease; for these glucocorticoid dosages, monitoring guidelines are being developed. In these situations, next to good clinical practice monitoring, including for instance blood pressure measurements, checks of ocular pressure and urine glucose specifically seem indicated. For clinical trials on glucocorticoids, it is advised to monitor and report more comprehensively and to sample more data on the spectrum, incidence, and severity of adverse events of glucocorticoids.67 If applied prudently, glucocorticoids are still one of the most relevant therapeutic tools in clinical medicine of the 21st century. Future Directions Although glucocorticoids have been used in clinical practice for many years, they still are the anchor drugs in autoimmune and inflammatory diseases and vasculitides. In contrast with their established use, there is a paucity of data on the spectrum, incidence, and severity of adverse effects of glucocorticoids at different dosages and in different diseases. To develop evidence-based guidelines and to evaluate the adverse effects of new compounds with glucocorticoid actions that are being developed, additional research into molecular mechanisms and continued collection of data are needed.67 References 1. Hench PS, Kendall EC, Slocumb CH, Polley HF: The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone: compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis: preliminary report, Proceedings Staff Meetings Mayo Clinic 24:181–197, 1949. 2. Buttgereit F, da Silva JA, Boers M, et al: Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology, Ann Rheum Dis 61:718–722, 2002. 3. Buttgereit F, Zhou H, Seibel MJ: Arthritis and endogenous glucocorticoids: the emerging role of the 11beta-HSD enzymes, Ann Rheum Dis 67:1201–1203, 2008. 4. Hardy R, Rabbitt EH, Filer A, et al: Local and systemic glucocorticoid metabolism in inflammatory arthritis, Ann Rheum Dis 67:1204–1210, 2008. 5. Buttgereit F, Wehling M, Burmester GR: A new hypothesis of modular glucocorticoid actions: steroid treatment of rheumatic diseases revisited, Arthritis Rheum 41:761–767, 1998. 6. Tornatore KM, Logue G, Venuto RC, Davis PJ: Pharmacokinetics of methylprednisolone in elderly and young healthy males, J Am Geriatr Soc 42:1118–1122, 1994. 7. Tornatore KM, Biocevich DM, Reed K, et al: Methylprednisolone pharmacokinetics, cortisol response, and adverse effects in black and white renal transplant recipients, Transplantation 59:729–736, 1995. 8. Carrie F, Roblot P, Bouquet S, et al: Rifampin-induced nonresponsiveness of giant cell arteritis to prednisone treatment, Arch Intern Med 154:1521–1524, 1994. 9. McAllister WA, Thompson PJ, Al Habet SM, Rogers HJ: Rifampicin reduces effectiveness and bioavailability of prednisolone, Br Med J (Clin Res Ed) 286:923–925, 1983. 10. Kyriazopoulou V, Parparousi O, Vagenakis AG: Rifampicin-induced adrenal crisis in addisonian patients receiving corticosteroid replacement therapy, J Clin Endocrinol Metab 59:1204–1206, 1984. 11. Bornstein SR: Predisposing factors for adrenal insufficiency, N Engl J Med 360:2328–2339, 2009. 12. Cooper MS, Stewart PM: Corticosteroid insufficiency in acutely ill patients, N Engl J Med 348:727–734, 2003. 13. Oerlemans R, Vink J, Dijkmans BA, et al: Sulfasalazine sensitises human monocytic/macrophage cells for glucocorticoids by upregulation of glucocorticoid receptor alpha and glucocorticoid induced apoptosis, Ann Rheum Dis 66:1289–1295, 2007. 914 PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS 14. Peltoniemi OM, Kari MA, Lano A, et al: Two-year follow-up of a randomised trial with repeated antenatal betamethasone, Arch Dis Child Fetal Neonatal Ed 94:F402–F406, 2009. 15. Wapner RJ, Sorokin Y, Mele L, et al: Long-term outcomes after repeat doses of antenatal corticosteroids, N Engl J Med 357:1190–1198, 2007. 16. Yeh TF, Lin YJ, Lin HC, et al: Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity, N Engl J Med 350:1304–1313, 2004. 17. Park-Wyllie L, Mazzotta P, Pastuszak A, et al: Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies, Teratology 62:385–392, 2000. 18. Temprano KK, Bandlamudi R, Moore TL: Antirheumatic drugs in pregnancy and lactation, Semin Arthritis Rheum 35:112–121, 2005. 19. Barnes PJ: Anti-inflammatory actions of glucocorticoids: molecular mechanisms, Clin Sci (Lond) 94:557–572, 1998. 20. Lipworth BJ: Therapeutic implications of non-genomic glucocorticoid activity, Lancet 356:87–89, 2000. 21. Rhen T, Cidlowski JA: Antiinflammatory action of glucocorticoids— new mechanisms for old drugs, N Engl J Med 353:1711–1723, 2005. 22. Ristimaki A, Narko K, Hla T: Down-regulation of cytokine-induced cyclo-oxygenase-2 transcript isoforms by dexamethasone: evidence for post-transcriptional regulation, Biochem J 318(Pt 1):325–331, 1996. 23. Tili E, Michaille JJ, Costinean S, Croce CM: MicroRNAs, the immune system and rheumatic disease, Nat Clin Pract Rheumatol 4:534–541, 2008. 24. Boumpas DT, Chrousos GP, Wilder RL, et al: Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates, Ann Intern Med 119:1198–1208, 1993. 25. Leonard JP, Silverstein RL: Corticosteroids and the haematopoietic system. In: Lin AN, Paget SA, editors: Principles of corticosteroid therapy, New York, 2002, Arnold, pp 144–149. 26. Verhoef CM, van Roon JA, Vianen ME, et al: The immune suppressive effect of dexamethasone in rheumatoid arthritis is accompanied by upregulation of interleukin 10 and by differential changes in interferon gamma and interleukin 4 production, Ann Rheum Dis 58:49–54, 1999. 27. Morand EF, Jefferiss CM, Dixey J, et al: Impaired glucocorticoid induction of mononuclear leukocyte lipocortin-1 in rheumatoid arthritis, Arthritis Rheum 37:207–211, 1994. 28. DiBattista JA, Martel-Pelletier J, Wosu LO, et al: Glucocorticoid receptor mediated inhibition of interleukin-1 stimulated neutral metalloprotease synthesis in normal human chondrocytes, J Clin Endocrinol Metab 72:316–326, 1991. 29. Cronstein BN, Kimmel SC, Levin RI, et al: A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1, Proc Natl Acad Sci U S A 89:9991–9995, 1992. 30. Di Rosa M, Radomski M, Carnuccio R, Moncada S: Glucocorticoids inhibit the induction of nitric oxide synthase in macrophages, Biochem Biophys Res Commun 172:1246–1252, 1990. 31. Neeck G: Fifty years of experience with cortisone therapy in the study and treatment of rheumatoid arthritis, Ann N Y Acad Sci 966:28–38, 2002. 32. Gudbjornsson B, Skogseid B, Oberg K, et al: Intact adrenocorticotropic hormone secretion but impaired cortisol response in patients with active rheumatoid arthritis: effect of glucocorticoids, J Rheumatol 23:596–602, 1996. 33. Chikanza IC, Petrou P, Kingsley G, et al: Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis, Arthritis Rheum 35:1281–1288, 1992. 34. Bijlsma JW, Cutolo M, Masi AT, Chikanza IC: The neuroendocrine immune basis of rheumatic diseases, Immunol Today 20:298–301, 1999. 35. Arlt W: The approach to the adult with newly diagnosed adrenal insufficiency, J Clin Endocrinol Metab 94:1059–1067, 2009. 36. Debono M, Ross RJ, Newell-Price J: Inadequacies of glucocorticoid replacement and improvements by physiological circadian therapy, Eur J Endocrinol 160:719–729, 2009. 37. Anonymous: AHFS drug information, Bethesda, Md, 2001, American Hospital Formulary Service. 38. Ackerman GL, Nolsn CM: Adrenocortical responsiveness after alternate-day corticosteroid therapy, N Engl J Med 278:405–409, 1968. 39. Schlaghecke R, Kornely E, Santen RT, Ridderskamp P: The effect of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropin-releasing hormone, N Engl J Med 326:226– 230, 1992. 40. Henzen C, Suter A, Lerch E, et al: Suppression and recovery of adrenal response after short-term, high-dose glucocorticoid treatment, Lancet 355:542–545, 2000. 41. Gaffney K, Ledingham J, Perry JD: Intra-articular triamcinolone hexacetonide in knee osteoarthritis: factors influencing the clinical response, Ann Rheum Dis 54:379–381, 1995. 42. Jacobs JWG: How to perform local soft-tissue glucocorticoid injections, Best Pract Res Clin Rheumatol 23:193–219, 2009. 43. Weinblatt ME, Kremer JM, Coblyn JS, et al: Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis, Arthritis Rheum 42:1322–1328, 1999. 44. Smolen JS, Kalden JR, Scott DL, et al: Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group, Lancet 353:259–266, 1999. 45. Wolfe F, Caplan L, Michaud K: Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy, Arthritis Rheum 54:628–634, 2006. 46. Huscher D, Thiele K, Gromnica-Ihle E, et al: Dose-related patterns of glucocorticoid-induced side effects, Ann Rheum Dis 68:1119–1124, 2009. 47. ACR Subcommittee on Rheumatoid Arthritis Guidelines: Guidelines for the management of rheumatoid arthritis: 2002 update, Arthritis Rheum 46:328–346, 2002. 48. Criswell LA, Saag KG, Sems KM, et al: Moderate-term, low-dose corticosteroids for rheumatoid arthritis, Cochrane Database Syst Rev (2):CD001158, 2000. 49. Kirwan JR: The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The Arthritis and Rheumatism Council LowDose Glucocorticoid Study Group, N Engl J Med 333:142–146, 1995. 50. Boers M, Verhoeven AC, Markusse HM, et al: Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis, Lancet 350:309–318, 1997. 51. Landewé RB, Boers M, Verhoeven AC, et al: COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention, Arthritis Rheum 46:347–356, 2002. 52. Haagsma CJ, van Riel PL, de Jong AJ, van de Putte LB: Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial, Br J Rheumatol 36:1082–1088, 1997. 53. Dougados M, Combe B, Cantagrel A, et al: Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components, Ann Rheum Dis 58:220–225, 1999. 54. Goekoop-Ruiterman YP, Vries-Bouwstra JK, Allaart CF, et al: Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial, Arthritis Rheum 52:3381–3390, 2005. 55. Wassenberg S, Rau R, Steinfeld P, Zeidler H: Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, double-blind, placebo-controlled trial, Arthritis Rheum 52:3371–3380, 2005. 56. Van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, Bijlsma JW: Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial, Ann Intern Med 136:1–12, 2002. 57. Jacobs JW, Van Everdingen AA, Verstappen SM, Bijlsma JW: Followup radiographic data on patients with rheumatoid arthritis who participated in a two-year trial of prednisone therapy or placebo, Arthritis Rheum 54:1422–1428, 2006. 58. Svensson B, Boonen A, Albertsson K, et al: Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in CHAPTER 60 patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a two-year randomized trial, Arthritis Rheum 52:3360–3370, 2005. 58a. Bakker MF, Jacobs JWG, Welsing PM, et al: Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis. A randomized trial, Ann Intern Med 156:329– 339, 2012. 59. Hansen M, Podenphant J, Florescu A, et al: A randomised trial of differentiated prednisolone treatment in active rheumatoid arthritis: clinical benefits and skeletal side effects, Ann Rheum Dis 58:713–718, 1999. 60. Paulus HE, Di Primeo D, Sanda M, et al: Progression of radiographic joint erosion during low dose corticosteroid treatment of rheumatoid arthritis, J Rheumatol 27:1632–1637, 2000. 61. Capell HA, Madhok R, Hunter JA, et al: Lack of radiological and clinical benefit over two years of low dose prednisolone for rheumatoid arthritis: results of a randomised controlled trial, Ann Rheum Dis 63:797–803, 2004. 62. Kirwan JR, Bijlsma JW, Boers M, Shea BJ: Effects of glucocorticoids on radiological progression in rheumatoid arthritis, Cochrane Database Syst Rev (1):CD006356, 2007. 63. O’Dell JR: Treating rheumatoid arthritis early: a window of opportunity? Arthritis Rheum 46:283–285, 2002. 64. Moreland LW, Curtis JR: Systemic nonarticular manifestations of rheumatoid arthritis: focus on inflammatory mechanisms, Semin Arthritis Rheum 39:132–143, 2009. 65. Fries JF, Williams CA, Ramey D, Bloch DA: The relative toxicity of disease-modifying antirheumatic drugs, Arthritis Rheum 36:297–306, 1993. 66. da Silva JAP, Jacobs JWG, Kirwan JR, et al: Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data, Ann Rheum Dis 65:285–293, 2006. 66a. Smolen JS, Landewé R, Breedveld FC, et al: EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs, Ann Rheum Dis 69:64–75, 2010. 67. van der Goes MC, Jacobs JWG, Boers M, et al: Monitoring adverse events of low-dose glucocorticoids therapy: EULAR recommendations for clinical trials and daily practice, Ann Rheum Dis 69:1913– 1919, 2010. 68. Hoes JN, Jacobs JW, Boers M, et al: EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases, Ann Rheum Dis 66:1560–1567, 2007. 69. Bos WH, Dijkmans BA, Boers M, et al: Effect of dexamethasone on autoantibody levels and arthritis development in patients with arthralgia: a randomised trial, Ann Rheum Dis 69:571–574, 2010. 70. Machold KP, Landewe R, Smolen JS, et al: The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis, Ann Rheum Dis 69:495–502, 2010. 71. Verstappen SM, McCoy MJ, Roberts C, et al: Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial, Ann Rheum Dis 69:503–509, 2010. 72. Arvidson NG, Gudbjornsson B, Larsson A, Hallgren R: The timing of glucocorticoid administration in rheumatoid arthritis, Ann Rheum Dis 56:27–31, 1997. 73. Kowanko IC, Pownall R, Knapp MS, et al: Time of day of prednisolone administration in rheumatoid arthritis, Ann Rheum Dis 41:447– 452, 1982. 74. Buttgereit F, Doering G, Schaeffler A, et al: Efficacy of modifiedrelease versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a doubleblind, randomised controlled trial, Lancet 371:205–214, 2008. 75. Bijlsma JW, Jacobs JW: Glucocorticoid chronotherapy in rheumatoid arthritis, Lancet 371:183–184, 2008. 76. Eberhardt R, Kruger K, Reiter W, et al: Long-term therapy with the new glucocorticosteroid deflazacort in rheumatoid arthritis: doubleblind controlled randomized 12-months study against prednisone, Arzneimittelforschung 44:642–647, 1994. 77. Saviola G, Abdi AL, Shams ES, et al: Compared clinical efficacy and bone metabolic effects of low-dose deflazacort and methyl prednisolone in male inflammatory arthropathies: a 12-month open randomized pilot study, Rheumatology (Oxford) 46:994–998, 2007. | Glucocorticoid Therapy 915 78. Buttgereit F, Burmester GR, Lipworth BJ: Optimised glucocorticoid therapy: the sharpening of an old spear, Lancet 365:801–803, 2005. 79. Paul-Clark MJ, Mancini L, Del Soldato P, et al: Potent antiarthritic properties of a glucocorticoid derivative, NCX-1015, in an experimental model of arthritis, Proc Natl Acad Sci U S A 99:1677–1682, 2002. 80. Zimmermann GR, Avery W, Finelli AL, et al: Selective amplification of glucocorticoid anti-inflammatory activity through synergistic multi-target action of a combination drug, Arthritis Res Ther 11:R12, 2009. 81. Jacobs JW, Bijlsma JW: Innovative combination strategy to enhance effect and diminish adverse effects of glucocorticoids: another promise? Arthritis Res Ther 11:105, 2009. 82. Koning GA, Schiffelers RM, Wauben MH, et al: Targeting of angiogenic endothelial cells at sites of inflammation by dexamethasone phosphate-containing RGD peptide liposomes inhibits experimental arthritis, Arthritis Rheum 54:1198–1208, 2006. 83. Barrera P: Long-circulating liposomal prednisolone versus pulse intramuscular methylprednisolone in patients with active rheumatoid arthritis, Arthritis Rheum 58(Suppl):S453, 2008. 84. Hunder GG, Sheps SG, Allen GL, Joyce JW: Daily and alternate-day corticosteroid regimens in treatment of giant cell arteritis: comparison in a prospective study, Ann Intern Med 82:613–618, 1975. 85. Bengtsson BA, Malmvall BE: An alternate-day corticosteroid regimen in maintenance therapy of giant cell arteritis, Acta Med Scand 209:347–350, 1981. 86. Avioli LV: Glucocorticoid effects on statural growth, Br J Rheumatol 32(Suppl 2):27–30, 1993. 87. Barnes PJ, Adcock IM: Glucocorticoid resistance in inflammatory diseases, Lancet 373:1905–1917, 2009. 88. Basta-Kaim A, Budziszewska B, Jaworska-Feil L, et al: Chlorpromazine inhibits the glucocorticoid receptor-mediated gene transcription in a calcium-dependent manner, Neuropharmacology 43:1035–1043, 2002. 89. Salem M, Tainsh RE Jr, Bromberg J, et al: Perioperative glucocorticoid coverage: a reassessment 42 years after emergence of a problem, Ann Surg 219:416–425, 1994. 90. Marik PE, Varon J: Requirement of perioperative stress doses of corticosteroids: a systematic review of the literature, Arch Surg 143:1222–1226, 2008. 91. Furst DE, Keystone EC, Fleischmann R, et al: Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2009, Ann Rheum Dis 69(Suppl 1):i2–i29, 2010. 92. Weusten BL, Jacobs JW, Bijlsma JW: Corticosteroid pulse therapy in active rheumatoid arthritis, Semin Arthritis Rheum 23:183–192, 1993. 93. Jacobs JW, Geenen R, Evers AW, et al: Short term effects of corticosteroid pulse treatment on disease activity and the wellbeing of patients with active rheumatoid arthritis, Ann Rheum Dis 60:61–64, 2001. 94. Hayreh SS, Zimmerman B: Visual deterioration in giant cell arteritis patients while on high doses of corticosteroid therapy, Ophthalmology 110:1204–1215, 2003. 95. Hepper CT, Halvorson JJ, Duncan ST, et al: The efficacy and duration of intra-articular corticosteroid injection for knee osteoarthritis: a systematic review of level I studies, J Am Acad Orthop Surg 17:638– 646, 2009. 96. Eustace JA, Brophy DP, Gibney RP, et al: Comparison of the accuracy of steroid placement with clinical outcome in patients with shoulder symptoms, Ann Rheum Dis 56:59–63, 1997. 97. Jones A, Regan M, Ledingham J, et al: Importance of placement of intra-articular steroid injections, BMJ 307:1329–1330, 1993. 98. Gray RG, Gottlieb NL: Intra-articular corticosteroids: an updated assessment, Clin Orthop Relat Res 177:235–263, 1983. 99. Seror P, Pluvinage P, d’Andre FL, et al: Frequency of sepsis after local corticosteroid injection (an inquiry on 1160000 injections in rheumatological private practice in France), Rheumatology (Oxford) 38:1272–1274, 1999. 100. Kaandorp CJ, Krijnen P, Moens HJ, et al: The outcome of bacterial arthritis: a prospective community-based study, Arthritis Rheum 40:884–892, 1997. 101. Huscher D, Thiele K, Gromnica-Ihle E, et al: Dose-related patterns of glucocorticoid-induced side effects, Ann Rheum Dis 68:1119–1124, 2009. 916 PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS 102. Ravindran V, Rachapalli S, Choy EH: Safety of medium- to longterm glucocorticoid therapy in rheumatoid arthritis: a meta-analysis, Rheumatology (Oxford) 48:807–811, 2009. 103. van der Goes MC, Jacobs JW, Boers M, et al: Patient and rheumatologist perspectives on glucocorticoids: an exercise to improve the implementation of the European League Against Rheumatism (EULAR) recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases, Ann Rheum Dis 69:1015– 1021, 2010. 104. Hoes JN, Jacobs JW, Verstappen SM, et al: Adverse events of low-to-medium-dose oral glucocorticoids in inflammatory diseases: a meta-analysis, Ann Rheum Dis 68:1833–1838, 2009. 105. Grossman JM, Gordon R, Ranganath VK, et al: American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis, Arthritis Rheum 62:1515–1526, 2010. 106. Abadie EC, Devogealer JP, Ringe JD, et al: Recommendations for the registration of agents to be used in the prevention and treatment of glucocorticoid-induced osteoporosis: updated recommendations from the Group for the Respect of Ethics and Excellence in Science, Semin Arthritis Rheum 35:1–4, 2005. 107. Garcia Rodriguez LA, Hernandez-Diaz S: The risk of upper gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs, glucocorticoids, acetaminophen, and combinations of these agents, Arthritis Res 3:98–101, 2001. 108. Piper JM, Ray WA, Daugherty JR, Griffin MR: Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs, Ann Intern Med 114:735–740, 1991. 109. Saab S, Corr MP, Weisman MH: Corticosteroids and systemic lupus erythematosus pancreatitis: a case series, J Rheumatol 25:801–806, 1998. 110. Stuck AE, Minder CE, Frey FJ: Risk of infectious complications in patients taking glucocorticosteroids, Rev Infect Dis 11:954–963, 1989. 111. Panoulas VF, Douglas KM, Stavropoulos-Kalinoglou A, et al: Longterm exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis, Rheumatology (Oxford) 47:72–75, 2008. 112. Mason JW, O’Connell JB, Herskowitz A, et al: A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators, N Engl J Med 333:269–275, 1995. 113. Latham RD, Mulrow JP, Virmani R, et al: Recently diagnosed idiopathic dilated cardiomyopathy: incidence of myocarditis and efficacy of prednisone therapy, Am Heart J 117:876–882, 1989. 114. Peters MJ, Symmons DP, McCarey D, et al: EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis, Ann Rheum Dis 69:325–331, 2010. 115. Wei L, MacDonald TM, Walker BR: Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease, Ann Intern Med 141:764–770, 2004. 116. Poon M, Gertz SD, Fallon JT, et al: Dexamethasone inhibits macrophage accumulation after balloon arterial injury in cholesterol fed rabbits, Atherosclerosis 155:371–380, 2001. 117. Dessein PH, Stanwix AE, Joffe BI: Cardiovascular risk in rheumatoid arthritis versus osteoarthritis: acute phase response related decreased insulin sensitivity and high-density lipoprotein cholesterol as well as clustering of metabolic syndrome features in rheumatoid arthritis, Arthritis Res 4:R5, 2002. 118. Park YB, Choi HK, Kim MY, et al: Effects of antirheumatic therapy on serum lipid levels in patients with rheumatoid arthritis: a prospective study, Am J Med 113:188–193, 2002. 119. Garcia-Gomez C, Nolla JM, Valverde J, et al: High HDL-cholesterol in women with rheumatoid arthritis on low-dose glucocorticoid therapy, Eur J Clin Invest 38:686–692, 2008. 120. Davis JM III, Maradit-Kremers H, Gabriel SE: Use of low-dose glucocorticoids and the risk of cardiovascular morbidity and mortality in rheumatoid arthritis: what is the true direction of effect? J Rheumatol 32:1856–1862, 2005. 121. Otte C, Wust S, Zhao S, et al: Glucocorticoid receptor gene, lowgrade inflammation, and heart failure: the Heart and Soul study, J Clin Endocrinol Metab 95:2885–2891, 2010. 122. Carnahan MC, Goldstein DA: Ocular complications of topical, periocular, and systemic corticosteroids, Curr Opin Ophthalmol 11:478– 483, 2000. 123. Klein BE, Klein R, Lee KE, Danforth LG: Drug use and five-year incidence of age-related cataracts: the Beaver Dam Eye study, Ophthalmology 108:1670–1674, 2001. 124. Garbe E, LeLorier J, Boivin JF, Suissa S: Risk of ocular hypertension or open-angle glaucoma in elderly patients on oral glucocorticoids, Lancet 350:979–982, 1997. 125. Tripathi RC, Parapuram SK, Tripathi BJ, et al: Corticosteroids and glaucoma risk, Drugs Aging 15:439–450, 1999. 126. Gurwitz JH, Bohn RL, Glynn RJ, et al: Glucocorticoids and the risk for initiation of hypoglycemic therapy, Arch Intern Med 154:97–101, 1994. 127. Stewart PM, Tomlinson JW: Cortisol, 11 beta-hydroxysteroid dehydrogenase type 1 and central obesity, Trends Endocrinol Metab 13:94– 96, 2002. 128. Oelkers W: Adrenal insufficiency, N Engl J Med 335:1206–1212, 1996. 129. Sampson PA, Brooke BN, Winstone NE: Biochemical conformation of collapse due to adrenal failure, Lancet i:1377, 1961. 130. Patten SB, Neutel CI: Corticosteroid-induced adverse psychiatric effects: incidence, diagnosis and management, Drug Saf 22:111–122, 2000. 131. Naber D, Sand P, Heigl B: Psychopathological and neuropsychological effects of 8-days’ corticosteroid treatment: a prospective study, Psychoneuroendocrinology 21:25–31, 1996. The references for this chapter can also be found on www.expertconsult.com. CHAPTER 60 References 1. Hench PS, Kendall EC, Slocumb CH, Polley HF: The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone: compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis: preliminary report, Proceedings Staff Meetings Mayo Clinic 24:181–197, 1949. 2. Buttgereit F, da Silva JA, Boers M, et al: Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology, Ann Rheum Dis 61:718–722, 2002. 3. Buttgereit F, Zhou H, Seibel MJ: Arthritis and endogenous glucocorticoids: the emerging role of the 11beta-HSD enzymes, Ann Rheum Dis 67:1201–1203, 2008. 4. Hardy R, Rabbitt EH, Filer A, et al: Local and systemic glucocorticoid metabolism in inflammatory arthritis, Ann Rheum Dis 67:1204–1210, 2008. 5. Buttgereit F, Wehling M, Burmester GR: A new hypothesis of modular glucocorticoid actions: steroid treatment of rheumatic diseases revisited, Arthritis Rheum 41:761–767, 1998. 6. Tornatore KM, Logue G, Venuto RC, Davis PJ: Pharmacokinetics of methylprednisolone in elderly and young healthy males, J Am Geriatr Soc 42:1118–1122, 1994. 7. Tornatore KM, Biocevich DM, Reed K, et al: Methylprednisolone pharmacokinetics, cortisol response, and adverse effects in black and white renal transplant recipients, Transplantation 59:729–736, 1995. 8. Carrie F, Roblot P, Bouquet S, et al: Rifampin-induced nonresponsiveness of giant cell arteritis to prednisone treatment, Arch Intern Med 154:1521–1524, 1994. 9. McAllister WA, Thompson PJ, Al Habet SM, Rogers HJ: Rifampicin reduces effectiveness and bioavailability of prednisolone, Br Med J (Clin Res Ed) 286:923–925, 1983. 10. Kyriazopoulou V, Parparousi O, Vagenakis AG: Rifampicin-induced adrenal crisis in addisonian patients receiving corticosteroid replacement therapy, J Clin Endocrinol Metab 59:1204–1206, 1984. 11. Bornstein SR: Predisposing factors for adrenal insufficiency, N Engl J Med 360:2328–2339, 2009. 12. Cooper MS, Stewart PM: Corticosteroid insufficiency in acutely ill patients, N Engl J Med 348:727–734, 2003. 13. Oerlemans R, Vink J, Dijkmans BA, et al: Sulfasalazine sensitises human monocytic/macrophage cells for glucocorticoids by upregulation of glucocorticoid receptor alpha and glucocorticoid induced apoptosis, Ann Rheum Dis 66:1289–1295, 2007. 14. Peltoniemi OM, Kari MA, Lano A, et al: Two-year follow-up of a randomised trial with repeated antenatal betamethasone, Arch Dis Child Fetal Neonatal Ed 94:F402–F406, 2009. 15. Wapner RJ, Sorokin Y, Mele L, et al: Long-term outcomes after repeat doses of antenatal corticosteroids, N Engl J Med 357:1190–1198, 2007. 16. Yeh TF, Lin YJ, Lin HC, et al: Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity, N Engl J Med 350:1304–1313, 2004. 17. Park-Wyllie L, Mazzotta P, Pastuszak A, et al: Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies, Teratology 62:385–392, 2000. 18. Temprano KK, Bandlamudi R, Moore TL: Antirheumatic drugs in pregnancy and lactation, Semin Arthritis Rheum 35:112–121, 2005. 19. Barnes PJ: Anti-inflammatory actions of glucocorticoids: molecular mechanisms, Clin Sci (Lond) 94:557–572, 1998. 20. Lipworth BJ: Therapeutic implications of non-genomic glucocorticoid activity, Lancet 356:87–89, 2000. 21. Rhen T, Cidlowski JA: Antiinflammatory action of glucocorticoids— new mechanisms for old drugs, N Engl J Med 353:1711–1723, 2005. 22. Ristimaki A, Narko K, Hla T: Down-regulation of cytokine-induced cyclo-oxygenase-2 transcript isoforms by dexamethasone: evidence for post-transcriptional regulation, Biochem J 318(Pt 1):325–331, 1996. 23. Tili E, Michaille JJ, Costinean S, Croce CM: MicroRNAs, the immune system and rheumatic disease, Nat Clin Pract Rheumatol 4:534–541, 2008. 24. Boumpas DT, Chrousos GP, Wilder RL, et al: Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates, Ann Intern Med 119:1198–1208, 1993. | Glucocorticoid Therapy 916.e1 25. Leonard JP, Silverstein RL: Corticosteroids and the haematopoietic system. In: Lin AN, Paget SA, editors: Principles of corticosteroid therapy, New York, 2002, Arnold, pp 144–149. 26. Verhoef CM, van Roon JA, Vianen ME, et al: The immune suppressive effect of dexamethasone in rheumatoid arthritis is accompanied by upregulation of interleukin 10 and by differential changes in interferon gamma and interleukin 4 production, Ann Rheum Dis 58:49–54, 1999. 27. Morand EF, Jefferiss CM, Dixey J, et al: Impaired glucocorticoid induction of mononuclear leukocyte lipocortin-1 in rheumatoid arthritis, Arthritis Rheum 37:207–211, 1994. 28. DiBattista JA, Martel-Pelletier J, Wosu LO, et al: Glucocorticoid receptor mediated inhibition of interleukin-1 stimulated neutral metalloprotease synthesis in normal human chondrocytes, J Clin Endocrinol Metab 72:316–326, 1991. 29. Cronstein BN, Kimmel SC, Levin RI, et al: A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1, Proc Natl Acad Sci U S A 89:9991– 9995, 1992. 30. Di Rosa M, Radomski M, Carnuccio R, Moncada S: Glucocorticoids inhibit the induction of nitric oxide synthase in macrophages, Biochem Biophys Res Commun 172:1246–1252, 1990. 31. Neeck G: Fifty years of experience with cortisone therapy in the study and treatment of rheumatoid arthritis, Ann N Y Acad Sci 966:28–38, 2002. 32. Gudbjornsson B, Skogseid B, Oberg K, et al: Intact adrenocorticotropic hormone secretion but impaired cortisol response in patients with active rheumatoid arthritis: effect of glucocorticoids, J Rheumatol 23:596–602, 1996. 33. Chikanza IC, Petrou P, Kingsley G, et al: Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis, Arthritis Rheum 35:1281–1288, 1992. 34. Bijlsma JW, Cutolo M, Masi AT, Chikanza IC: The neuroendocrine immune basis of rheumatic diseases, Immunol Today 20:298–301, 1999. 35. Arlt W: The approach to the adult with newly diagnosed adrenal insufficiency, J Clin Endocrinol Metab 94:1059–1067, 2009. 36. Debono M, Ross RJ, Newell-Price J: Inadequacies of glucocorticoid replacement and improvements by physiological circadian therapy, Eur J Endocrinol 160:719–729, 2009. 37. Anonymous: AHFS drug information, Bethesda, Md, 2001, American Hospital Formulary Service. 38. Ackerman GL, Nolsn CM: Adrenocortical responsiveness after alternate-day corticosteroid therapy, N Engl J Med 278:405–409, 1968. 39. Schlaghecke R, Kornely E, Santen RT, Ridderskamp P: The effect of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropin-releasing hormone, N Engl J Med 326:226– 230, 1992. 40. Henzen C, Suter A, Lerch E, et al: Suppression and recovery of adrenal response after short-term, high-dose glucocorticoid treatment, Lancet 355:542–545, 2000. 41. Gaffney K, Ledingham J, Perry JD: Intra-articular triamcinolone hexacetonide in knee osteoarthritis: factors influencing the clinical response, Ann Rheum Dis 54:379–381, 1995. 42. Jacobs JWG: How to perform local soft-tissue glucocorticoid injections, Best Pract Res Clin Rheumatol 23:193–219, 2009. 43. Weinblatt ME, Kremer JM, Coblyn JS, et al: Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis, Arthritis Rheum 42:1322–1328, 1999. 44. Smolen JS, Kalden JR, Scott DL, et al: Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group, Lancet 353:259–266, 1999. 45. Wolfe F, Caplan L, Michaud K: Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy, Arthritis Rheum 54:628–634, 2006. 46. Huscher D, Thiele K, Gromnica-Ihle E, et al: Dose-related patterns of glucocorticoid-induced side effects, Ann Rheum Dis 68:1119–1124, 2009. 916.e2 PART 8 | PHARMACOLOGY OF ANTIRHEUMATIC DRUGS 47. ACR Subcommittee on Rheumatoid Arthritis Guidelines: Guidelines for the management of rheumatoid arthritis: 2002 update, Arthritis Rheum 46:328–346, 2002. 48. Criswell LA, Saag KG, Sems KM, et al: Moderate-term, low-dose corticosteroids for rheumatoid arthritis, Cochrane Database Syst Rev (2):CD001158, 2000. 49. Kirwan JR: The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The Arthritis and Rheumatism Council LowDose Glucocorticoid Study Group, N Engl J Med 333:142–146, 1995. 50. Boers M, Verhoeven AC, Markusse HM, et al: Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis, Lancet 350:309–318, 1997. 51. Landewé RB, Boers M, Verhoeven AC, et al: COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention, Arthritis Rheum 46:347–356, 2002. 52. Haagsma CJ, van Riel PL, de Jong AJ, van de Putte LB: Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial, Br J Rheumatol 36:1082–1088, 1997. 53. Dougados M, Combe B, Cantagrel A, et al: Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components, Ann Rheum Dis 58:220–225, 1999. 54. Goekoop-Ruiterman YP, Vries-Bouwstra JK, Allaart CF, et al: Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial, Arthritis Rheum 52:3381–3390, 2005. 55. Wassenberg S, Rau R, Steinfeld P, Zeidler H: Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, double-blind, placebo-controlled trial, Arthritis Rheum 52:3371–3380, 2005. 56. Van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, Bijlsma JW: Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial, Ann Intern Med 136:1–12, 2002. 57. Jacobs JW, Van Everdingen AA, Verstappen SM, Bijlsma JW: Followup radiographic data on patients with rheumatoid arthritis who participated in a two-year trial of prednisone therapy or placebo, Arthritis Rheum 54:1422–1428, 2006. 58. Svensson B, Boonen A, Albertsson K, et al: Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a two-year randomized trial, Arthritis Rheum 52:3360–3370, 2005. 58a. Bakker MF, Jacobs JWG, Welsing PM, et al: Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis. A randomized trial, Ann Intern Med 156:329– 339, 2012. 59. Hansen M, Podenphant J, Florescu A, et al: A randomised trial of differentiated prednisolone treatment in active rheumatoid arthritis: clinical benefits and skeletal side effects, Ann Rheum Dis 58:713–718, 1999. 60. Paulus HE, Di Primeo D, Sanda M, et al: Progression of radiographic joint erosion during low dose corticosteroid treatment of rheumatoid arthritis, J Rheumatol 27:1632–1637, 2000. 61. Capell HA, Madhok R, Hunter JA, et al: Lack of radiological and clinical benefit over two years of low dose prednisolone for rheumatoid arthritis: results of a randomised controlled trial, Ann Rheum Dis 63:797–803, 2004. 62. Kirwan JR, Bijlsma JW, Boers M, Shea BJ: Effects of glucocorticoids on radiological progression in rheumatoid arthritis, Cochrane Database Syst Rev (1):CD006356, 2007. 63. O’Dell JR: Treating rheumatoid arthritis early: a window of opportunity? Arthritis Rheum 46:283–285, 2002. 64. Moreland LW, Curtis JR: Systemic nonarticular manifestations of rheumatoid arthritis: focus on inflammatory mechanisms, Semin Arthritis Rheum 39:132–143, 2009. 65. Fries JF, Williams CA, Ramey D, Bloch DA: The relative toxicity of disease-modifying antirheumatic drugs, Arthritis Rheum 36:297–306, 1993. 66. da Silva JAP, Jacobs JWG, Kirwan JR, et al: Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data, Ann Rheum Dis 65:285–293, 2006. 66a. Smolen JS, Landewé R, Breedveld FC, et al: EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs, Ann Rheum Dis 69:64–75, 2010. 67. van der Goes MC, Jacobs JWG, Boers M, et al: Monitoring adverse events of low-dose glucocorticoids therapy: EULAR recommendations for clinical trials and daily practice, Ann Rheum Dis 69:1913– 1919, 2010. 68. Hoes JN, Jacobs JW, Boers M, et al: EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases, Ann Rheum Dis 66:1560–1567, 2007. 69. Bos WH, Dijkmans BA, Boers M, et al: Effect of dexamethasone on autoantibody levels and arthritis development in patients with arthralgia: a randomised trial, Ann Rheum Dis 69:571–574, 2010. 70. Machold KP, Landewe R, Smolen JS, et al: The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis, Ann Rheum Dis 69:495–502, 2010. 71. Verstappen SM, McCoy MJ, Roberts C, et al: Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial, Ann Rheum Dis 69:503–509, 2010. 72. Arvidson NG, Gudbjornsson B, Larsson A, Hallgren R: The timing of glucocorticoid administration in rheumatoid arthritis, Ann Rheum Dis 56:27–31, 1997. 73. Kowanko IC, Pownall R, Knapp MS, et al: Time of day of prednisolone administration in rheumatoid arthritis, Ann Rheum Dis 41:447– 452, 1982. 74. Buttgereit F, Doering G, Schaeffler A, et al: Efficacy of modifiedrelease versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a doubleblind, randomised controlled trial, Lancet 371:205–214, 2008. 75. Bijlsma JW, Jacobs JW: Glucocorticoid chronotherapy in rheumatoid arthritis, Lancet 371:183–184, 2008. 76. Eberhardt R, Kruger K, Reiter W, et al: Long-term therapy with the new glucocorticosteroid deflazacort in rheumatoid arthritis: doubleblind controlled randomized 12-months study against prednisone, Arzneimittelforschung 44:642–647, 1994. 77. Saviola G, Abdi AL, Shams ES, et al: Compared clinical efficacy and bone metabolic effects of low-dose deflazacort and methyl prednisolone in male inflammatory arthropathies: a 12-month open randomized pilot study, Rheumatology (Oxford) 46:994–998, 2007. 78. Buttgereit F, Burmester GR, Lipworth BJ: Optimised glucocorticoid therapy: the sharpening of an old spear, Lancet 365:801–803, 2005. 79. Paul-Clark MJ, Mancini L, Del Soldato P, et al: Potent antiarthritic properties of a glucocorticoid derivative, NCX-1015, in an experimental model of arthritis, Proc Natl Acad Sci U S A 99:1677–1682, 2002. 80. Zimmermann GR, Avery W, Finelli AL, et al: Selective amplification of glucocorticoid anti-inflammatory activity through synergistic multi-target action of a combination drug, Arthritis Res Ther 11:R12, 2009. 81. Jacobs JW, Bijlsma JW: Innovative combination strategy to enhance effect and diminish adverse effects of glucocorticoids: another promise? Arthritis Res Ther 11:105, 2009. 82. Koning GA, Schiffelers RM, Wauben MH, et al: Targeting of angiogenic endothelial cells at sites of inflammation by dexamethasone phosphate-containing RGD peptide liposomes inhibits experimental arthritis, Arthritis Rheum 54:1198–1208, 2006. 83. Barrera P: Long-circulating liposomal prednisolone versus pulse intramuscular methylprednisolone in patients with active rheumatoid arthritis, Arthritis Rheum 58(Suppl):S453, 2008. 84. Hunder GG, Sheps SG, Allen GL, Joyce JW: Daily and alternateday corticosteroid regimens in treatment of giant cell arteritis: comparison in a prospective study, Ann Intern Med 82:613–618, 1975. 85. Bengtsson BA, Malmvall BE: An alternate-day corticosteroid regimen in maintenance therapy of giant cell arteritis, Acta Med Scand 209:347–350, 1981. 86. Avioli LV: Glucocorticoid effects on statural growth, Br J Rheumatol 32(Suppl 2):27–30, 1993. CHAPTER 60 87. Barnes PJ, Adcock IM: Glucocorticoid resistance in inflammatory diseases, Lancet 373:1905–1917, 2009. 88. Basta-Kaim A, Budziszewska B, Jaworska-Feil L, et al: Chlorpromazine inhibits the glucocorticoid receptor-mediated gene transcription in a calcium-dependent manner, Neuropharmacology 43:1035–1043, 2002. 89. Salem M, Tainsh RE Jr, Bromberg J, et al: Perioperative glucocorticoid coverage: a reassessment 42 years after emergence of a problem, Ann Surg 219:416–425, 1994. 90. Marik PE, Varon J: Requirement of perioperative stress doses of corticosteroids: a systematic review of the literature, Arch Surg 143:1222–1226, 2008. 91. Furst DE, Keystone EC, Fleischmann R, et al: Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2009, Ann Rheum Dis 69(Suppl 1):i2–i29, 2010. 92. Weusten BL, Jacobs JW, Bijlsma JW: Corticosteroid pulse therapy in active rheumatoid arthritis, Semin Arthritis Rheum 23:183–192, 1993. 93. Jacobs JW, Geenen R, Evers AW, et al: Short term effects of corticosteroid pulse treatment on disease activity and the wellbeing of patients with active rheumatoid arthritis, Ann Rheum Dis 60:61–64, 2001. 94. Hayreh SS, Zimmerman B: Visual deterioration in giant cell arteritis patients while on high doses of corticosteroid therapy, Ophthalmology 110:1204–1215, 2003. 95. Hepper CT, Halvorson JJ, Duncan ST, et al: The efficacy and duration of intra-articular corticosteroid injection for knee osteoarthritis: a systematic review of level I studies, J Am Acad Orthop Surg 17:638– 646, 2009. 96. Eustace JA, Brophy DP, Gibney RP, et al: Comparison of the accuracy of steroid placement with clinical outcome in patients with shoulder symptoms, Ann Rheum Dis 56:59–63, 1997. 97. Jones A, Regan M, Ledingham J, et al: Importance of placement of intra-articular steroid injections, BMJ 307:1329–1330, 1993. 98. Gray RG, Gottlieb NL: Intra-articular corticosteroids: an updated assessment, Clin Orthop Relat Res 177:235–263, 1983. 99. Seror P, Pluvinage P, d’Andre FL, et al: Frequency of sepsis after local corticosteroid injection (an inquiry on 1,160,000 injections in rheumatological private practice in France), Rheumatology (Oxford) 38:1272–1274, 1999. 100. Kaandorp CJ, Krijnen P, Moens HJ, et al: The outcome of bacterial arthritis: a prospective community-based study, Arthritis Rheum 40:884–892, 1997. 101. Huscher D, Thiele K, Gromnica-Ihle E, et al: Dose-related patterns of glucocorticoid-induced side effects, Ann Rheum Dis 68:1119–1124, 2009. 102. Ravindran V, Rachapalli S, Choy EH: Safety of medium- to longterm glucocorticoid therapy in rheumatoid arthritis: a meta-analysis, Rheumatology (Oxford) 48:807–811, 2009. 103. van der Goes MC, Jacobs JW, Boers M, et al: Patient and rheumatologist perspectives on glucocorticoids: an exercise to improve the implementation of the European League Against Rheumatism (EULAR) recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases, Ann Rheum Dis 69:1015– 1021, 2010. 104. Hoes JN, Jacobs JW, Verstappen SM, et al: Adverse events of lowto-medium-dose oral glucocorticoids in inflammatory diseases: a meta-analysis, Ann Rheum Dis 68:1833–1838, 2009. 105. Grossman JM, Gordon R, Ranganath VK, et al: American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis, Arthritis Rheum 62:1515–1526, 2010. 106. Abadie EC, Devogealer JP, Ringe JD, et al: Recommendations for the registration of agents to be used in the prevention and treatment of glucocorticoid-induced osteoporosis: updated recommendations from the Group for the Respect of Ethics and Excellence in Science, Semin Arthritis Rheum 35:1–4, 2005. 107. Garcia Rodriguez LA, Hernandez-Diaz S: The risk of upper gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs, glucocorticoids, acetaminophen, and combinations of these agents, Arthritis Res 3:98–101, 2001. 108. Piper JM, Ray WA, Daugherty JR, Griffin MR: Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs, Ann Intern Med 114:735–740, 1991. | Glucocorticoid Therapy 916.e3 109. Saab S, Corr MP, Weisman MH: Corticosteroids and systemic lupus erythematosus pancreatitis: a case series, J Rheumatol 25:801–806, 1998. 110. Stuck AE, Minder CE, Frey FJ: Risk of infectious complications in patients taking glucocorticosteroids, Rev Infect Dis 11:954–963, 1989. 111. Panoulas VF, Douglas KM, Stavropoulos-Kalinoglou A, et al: Longterm exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis, Rheumatology (Oxford) 47:72–75, 2008. 112. Mason JW, O’Connell JB, Herskowitz A, et al: A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators, N Engl J Med 333:269–275, 1995. 113. Latham RD, Mulrow JP, Virmani R, et al: Recently diagnosed idiopathic dilated cardiomyopathy: incidence of myocarditis and efficacy of prednisone therapy, Am Heart J 117:876–882, 1989. 114. Peters MJ, Symmons DP, McCarey D, et al: EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis, Ann Rheum Dis 69:325–331, 2010. 115. Wei L, MacDonald TM, Walker BR: Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease, Ann Intern Med 141:764–770, 2004. 116. Poon M, Gertz SD, Fallon JT, et al: Dexamethasone inhibits macrophage accumulation after balloon arterial injury in cholesterol fed rabbits, Atherosclerosis 155:371–380, 2001. 117. Dessein PH, Stanwix AE, Joffe BI: Cardiovascular risk in rheumatoid arthritis versus osteoarthritis: acute phase response related decreased insulin sensitivity and high-density lipoprotein cholesterol as well as clustering of metabolic syndrome features in rheumatoid arthritis, Arthritis Res 4:R5, 2002. 118. Park YB, Choi HK, Kim MY, et al: Effects of antirheumatic therapy on serum lipid levels in patients with rheumatoid arthritis: a prospective study, Am J Med 113:188–193, 2002. 119. Garcia-Gomez C, Nolla JM, Valverde J, et al: High HDL-cholesterol in women with rheumatoid arthritis on low-dose glucocorticoid therapy, Eur J Clin Invest 38:686–692, 2008. 120. Davis JM III, Maradit-Kremers H, Gabriel SE: Use of low-dose glucocorticoids and the risk of cardiovascular morbidity and mortality in rheumatoid arthritis: what is the true direction of effect? J Rheumatol 32:1856–1862, 2005. 121. Otte C, Wust S, Zhao S, et al: Glucocorticoid receptor gene, lowgrade inflammation, and heart failure: the Heart and Soul study, J Clin Endocrinol Metab 95:2885–2891, 2010. 122. Carnahan MC, Goldstein DA: Ocular complications of topical, periocular, and systemic corticosteroids, Curr Opin Ophthalmol 11:478– 483, 2000. 123. Klein BE, Klein R, Lee KE, Danforth LG: Drug use and five-year incidence of age-related cataracts: the Beaver Dam Eye study, Ophthalmology 108:1670–1674, 2001. 124. Garbe E, LeLorier J, Boivin JF, Suissa S: Risk of ocular hypertension or open-angle glaucoma in elderly patients on oral glucocorticoids, Lancet 350:979–982, 1997. 125. Tripathi RC, Parapuram SK, Tripathi BJ, et al: Corticosteroids and glaucoma risk, Drugs Aging 15:439–450, 1999. 126. Gurwitz JH, Bohn RL, Glynn RJ, et al: Glucocorticoids and the risk for initiation of hypoglycemic therapy, Arch Intern Med 154:97–101, 1994. 127. Stewart PM, Tomlinson JW: Cortisol, 11 beta-hydroxysteroid dehydrogenase type 1 and central obesity, Trends Endocrinol Metab 13:94– 96, 2002. 128. Oelkers W: Adrenal insufficiency, N Engl J Med 335:1206–1212, 1996. 129. Sampson PA, Brooke BN, Winstone NE: Biochemical conformation of collapse due to adrenal failure, Lancet i:1377, 1961. 130. Patten SB, Neutel CI: Corticosteroid-induced adverse psychiatric effects: incidence, diagnosis and management, Drug Saf 22:111–122, 2000. 131. Naber D, Sand P, Heigl B: Psychopathological and neuropsychological effects of 8-days’ corticosteroid treatment: a prospective study, Psychoneuroendocrinology 21:25–31, 1996.