Glucocorticoids (GC) continue to represent an important adjunct in the treatment of many rheumatic diseases, even if, with the availability of new immunosuppressants and biological therapies, their role is now less prominent than in the past.
A. Wesley Burks MD, in Middleton's Allergy: Principles and Practice, 2020
Infections and Relative Glucocorticosteroid Insensitivity
Up to 80% of asthma exacerbations in adults and children are associated with viral infections, particularly rhinovirus (RV).199 These infections are relatively refractory to high doses of ICS or OCS clinically, which correlates with the lack of effect of ICS on the expression of nasal inflammatory mediators.199 Experimental viral challenge is associated with enhanced oxidative and nitrosative stress and the reduction in HDAC2 expression in COPD patients, and it is likely that this is also the case in severe asthma.200
Corticosteroids also have little clinical benefit in bronchiolitis driven by respiratory syncytial virus (RSV). One action of RSV is to prevent GR nuclear translocation in nasopharyngeal aspirates from RSV-infected infants,201 confirming in vivo evidence previously reported in primary human bronchiolar epithelial cells by RV16.202 With RSV infection the mechanism involves competition of the viral nonstructural protein 1 with GR for importin 13 (IPO13) binding,201 whereas NF-κB and AP-1 pathways are associated with prevention of GR nuclear import, presumably because of changes in GR phosphorylation status, with RV16 infection.202
IFN-γ is induced by viral infection, and this is a dominant variable for chronic persistent obstruction in severe asthma.203 Previous studies have demonstrated that Th1 cytokines, such as TNF-α and IFN-γ, promote corticosteroid resistance in adult human ASM.74 This effect is related, in part, to the induction of interferon regulatory factor (IRF), which competes with GR for limit levels of the transcriptional co-regulator glutamate receptor–interacting protein (GRIP)-1.204 This relative steroid responsiveness is also seen in cells from children with steroid-refractory severe asthma and is selective because corticosteroid-induced gene expression is similar to that in cells from steroid responsive asthmatics.205 GR uses multiple mechanisms to suppress inflammatory gene expression, and activation of TLR9 drives inflammatory responses that are suppressed by activated GR. This effect is via a transcription-independent, rapid, and nongenomic GC suppression of TLR9 ligand-mediated IL-1R-associated kinase 1 (IRAK1) ubiquitination.206
It is evident that different genes within each cell type have a variable GR responsiveness and this also varies with cell type, which highlights the concept of pleiotropic gene- and cell-specific effects of dexamethasone.116 In A549 epithelial cells, this variable response to dexamethasone may reflect the relative requirement for the transcription factor IRF1 for inflammatory gene induction.207
Glucocorticoids reduce pain by decreasing inflammation.
Glucocorticoids have diverse and often deleterious effects on many tissues. Glucocorticoid administration can mask progression of the specific disease being treated and can also mask the development of new diseases (e.g., opportunistic infections).
Although glucocorticoids may play a role in the control of pain in some patients, they should be used sparingly and with caution.
The role of glucocorticoids for adjunctive analgesia and their use by novel routes (e.g., epidural administration) has not yet been thoroughly investigated in veterinary medicine.
As detailed previously, glucocorticoids are a major cause of and the most common etiology of medication-related secondary osteoporosis. Glucocorticoids are prescribed for a number of common inflammatory conditions, often in a chronic, long-term manner. They are potent suppressors of bone formation and at higher doses likely increase bone resorption, principally through central suppression of sex steroid production. This resultant “uncoupling” of bone turnover can result in dramatic declines in BMD within the first 6 months of starting therapy. In addition to bone loss, there is good evidence to support that individuals on glucocorticoids may fracture at a higher level on BMD compared with non-glucocorticoid-treated patients. Fracture rates are increased as well with doses of prednisone as low as 2.5 mg per day, although the increase in risk appears to attenuate with glucocorticoid discontinuation. The treatment approach to glucocorticoid-induced osteoporosis is similar to osteoporosis in general, with the exception that attempts should be made to reduce the steroid dose to as low as the underlying treated disease will permit.21 Calcium and vitamin D are important adjuncts but are insufficient to prevent bone loss or fractures. Although not clearly evidence-based, replacement of deficient sex steroids is a reasonable strategy in younger individuals who are at lower risk for fracture. The bisphosphonates alendronate, risedronate, and zoledronic acid are FDA approved for glucocorticoid-induced osteoporosis in women and men.A21 However, data suggest that either denosumab or teriparatide is superior to bisphosphanates for this purpose.A21b For example, 60 mg of subcutaneous denosumab every 6 months is superior to 5 mg oral risedronate daily at 12 months for its effect on BMD in patients with glucocorticoid-induced osteoporosis.A22 Teriparatide, which more directly addresses the osteoblast inhibition that is the primary mechanism of bone loss in glucocorticoid-induced osteoporosis, is superior to alendronate in improving BMD and reducing the risk of vertebral fractures in this situation.A23 Teriparitide should not be used for more than 24 months because of safety considerations.
Male osteoporosis historically has been underrecognized and underappreciated by primary care clinicians and patients alike, although the current data support a significantly more prevalent and clinically significant disorder. More than 2 million men in the United States have osteoporosis, and one in four men older than 50 years will suffer a fragility fracture in their remaining lifetime. Roughly 30% of vertebral and hip fractures combined occur in men, and these are the more common fractures in older men. In addition, men have a substantially higher mortality after hip fracture compared with women. As in women, aging, low body weight, and prior fragility fractures are independent predictors of fracture. In some contradistinction to women, however, osteoporosis in men is more commonly multifactorial in etiology, with the most common secondary causes being excess glucocorticoids, hypogonadism, and alcohol overuse. Despite these associations and others (current smoking, history of falls), there is not at present sufficient evidence to warrant use of a specific testing or screening strategy to identify men at higher risk for fracture. The laboratory work-up of male osteoporosis is similar to that for women, with the exception of a morning fasting testosterone level. Idiopathic osteoporosis may also occur, particularly in younger men with no discernable cause. Genetic factors may well be important in these men, with studies suggesting an association with lower production and circulating levels of estrogen. As in women, primary treatment of male osteoporosis is targeted at lifestyle changes, adequate nutrition (calcium and vitamin D), and exercise. Bisphosphonates (oral and intravenous), denosumab, and teriparatide are all effective at improving BMD in men, although a recent meta-analysis confirmed antifracture efficacy for vertebral and possibly for nonvertebral fractures with bisphosphonates alone, whereas the antifracture efficacy of nonbisphosphonates in men remains unconfirmed.A24 Although more limited in scope, antifracture efficacy appears evident for denosumab in men with prostate cancer on androgen deprivation therapy. True antifracture efficacy for the other agents and clinical scenarios is either less convincing or absent, based on the paucity of randomized controlled trial data, although this should not be construed as a reason not to treat. Testosterone replacement in men with significant biochemical hypogonadism (total T score <200 ng/dL) does improve bone density, although data on fracture risk reduction are lacking. In older men (>50 years) at a substantial risk for fracture based on history and risk factors, androgen replacement should be considered second line behind the aforementioned other therapies, based on overall risk-benefit and lack-of-fracture data.
Glucocorticoids (GCs) were first used for the treatment of inflammatory disease in the 1950s and have been heavily relied on for systemic lupus erythematosus (SLE) management across the seven decades since. Their potent antiinflammatory and immunosuppressive properties and rapid onset of action make GCs effective in suppressing SLE disease activity in many cases, and their use can be life or organ saving in patients with severe disease. However, their predictable and dose-dependent adverse effects make GCs a less than optimal treatment in SLE, especially for long-term use, and minimization is therefore a goal of SLE management. The clinical use of GCs in SLE, mechanisms of action, and adverse effects will be discussed in this chapter.
Osteoporosis is one of the most prevalent side effects in patients receiving long-term systemic glucocorticoid therapy. Without preventative measures, osteoporosis develops in 30–50% of all patients treated chronically with glucocorticoids15. A rapid decline in bone mineral density occurs within the first 3 months of usage, and the rate of loss peaks at 6 months16. Postmenopausal Caucasian women are at highest risk for complications such as fractures, because they have the lowest bone mass before beginning therapy. The greatest amount of bone loss is usually observed in young men, because they have the highest pretreatment bone mass. The development of osteopenia and osteoporosis is not avoided by alternate-morning treatment schedules.
Trabecular bone, which is present in the axial skeleton (vertebrae, ribs), has a metabolic turnover rate eight times that of cortical bone (long bones), making trabecular bone much more prone to demineralization17. Although many patients with osteoporosis have no symptoms, more advanced disease can produce bone pain, fractures, and vertebral collapse. The mechanism of glucocorticoid-induced bone loss includes both direct and indirect effects18. Glucocorticoidsdirectly reduce the proliferation and function of osteoblasts, increase apoptosis of osteoblasts, and promote proliferation of osteoclasts. They actindirectly by increasing urinary calcium excretion and reducing intestinal absorption of calcium. This decreases serum calcium and stimulates parathyroid hormone release, which drives osteoclasts to resorb bone.
Although routine radiographs can detect vertebral compression fractures, these plain X-ray studies are not sensitive enough to detect osteoporosis until 20–60% of bone mass is lost (Fig. 125.3). Currently, the best measurement of osteoporosis is quantification of bone mineral density with dual-energy X-ray absorptiometry (DEXA), which is preferred because of its sensitivity, reproducibility, and low radiation exposure. Ideally, patients on long-term glucocorticoids should have a baseline DEXA examination of the hip and lumbar spine, with a repeat study performed every 1–3 years at the same sites. In densitometry reports, T scores are used to connote a standard deviation from the mean of a healthy control population. Osteopenia is defined as a T score between −1 and −2.5 standard deviations below the mean, with a T score less than −2.5 defining osteoporosis15. For patients beginning long-term glucocorticoid therapy, risk factors for decreased bone density should be assessed and guidelines for the prevention and treatment of osteoporosis followed (Fig. 125.4)16,19. Endocrinologic consultation should be obtained in patients who develop significant osteopenia or osteoporosis. Further information on recommended regimens for osteoporosis prevention and treatment in patients receiving long-term glucocorticoid therapy is provided inFig. 125.419a.
Corticosteroids are the steroid molecules released from the adrenal gland in response to various stimuli. The mineralocorticoids (e.g., aldosterone) control the salt-retaining properties and will not be discussed in this chapter (although many of the synthetic corticosteroids used in therapy have some degree of mineralocorticoid activity). Glucocorticoids have their primary effect on metabolism, glucose, and inflammatory properties. This chapter will focus on those drugs. The other major corticosteroids are those that affect reproduction and have androgenic or estrogenic activity. These will not be discussed in this chapter.
Cortisol is the major naturally occurring glucocorticoid in animals (also called hydrocortisone). Its natural functions in the body are many, including intermediary metabolism. Cortisol is synthesized from cholesterol, and via a series of steps and intermediary steroids, it is eventually converted from cholesterol. Cortisol is secreted in the blood and is largely bound (> 90%) to plasma proteins, primarily corticosteroid-binding globulin. A smaller amount is bound to albumin, but with less affinity. Only the unbound portion is active for physiologic and pharmacologic actions, but the fraction bound to albumin is more readily available because of the low binding affinity. By contrast, synthetic glucocorticoids (e.g., dexamethasone) are bound to albumin rather than the corticosteroid-binding globulin.
Secretion of cortisol in people is estimated to be 10 to 20 mg/day (equivalent to 0.15 to 0.30 mg/kg/day) with peaks and troughs throughout the day that follow a circadian rhythm. These levels can rise 10-fold in the face of severe stress. Despite older reports that suggested diurnal rhythms in dogs and cats (and perhaps a reverse pattern in cats), no such pattern has been identified.1 In animals, the daily cortisol production in a nonstressed animal is approximately 1 mg/kg according to Ferguson and colleagues.1 These daily rates of production are important to note because this is the amount that must be replaced when states of adrenal insufficiency are treated.
Cortisol secretion in healthy animals is under tight regulatory control. Figure 13-1 shows the normal feedback and regulation. Secretion of cortisol exerts a negative feedback, ultimately reducing the secretion of cortisol. It is important to note that exogenous glucocorticosteroids (prednisolone, dexamethasone) also produce the same feedback, sometimes for several hours. Long-term treatment with glucocorticoids can therefore produce adrenal atrophy.
Glucocorticoids are the most consistently effective drugs available for the treatment of various forms of inflammation in animals. However, their potent anti-inflammatory effects and immunosuppressive actions must be balanced by their multiple side effects and adverse effects. In the past, clinicians referred to the action of glucocorticoids simply by saying that they “stabilize cell membranes.” Such a simplistic (and inaccurate) description of their cellular action no longer is appropriate. Glucocorticoids exert their action via binding to intracellular receptors, translocating to the nucleus, and binding to receptor sites on responsive genes, where they modulate the transcription of glucocorticoid-responsive genes2–7 (Figure 13-2). Through regulation of glucocorticoid-responsive genes, protein synthesis is altered, which affects cell function. These effects may be mediated by the interaction of glucocorticoids with activator protein 1 (AP-1) and nuclear factor κB (NF-κB) (see Figure 13-2). For control of inflammation, the major effect of corticosteroids is to inhibit synthesis of inflammatory mediators. This action of glucocorticoids is not immediate and may not become apparent for several hours. This is an important consideration if pharmacologic glucocorticoids are used in an acute or critical care situation in a veterinary hospital.
The action of glucocorticoids is complex and involves interactions with intracellular receptors and subsequent modulation of gene expression. Figure 13-3 shows the concept of transrepression and transactivation. Transrepression suppresses (“turns off”) expression of inflammatory products, such as cytokines, and cyclooxygenase-2 (COX-2), the enzyme that produces inflammatory prostaglandins. But glucocorticoids also cause transactivation, which produces metabolic changes that are responsible for many of the adverse effects of these agents. Although there have been many attempts over the years, no one has successfully produced a synthetic glucocorticoid that produces the beneficial changes (transrepression) while at the same time eliminating the negative effects (transactivation).
The dosage of GCs used often increases based on clinical activity and severity of the RA.3,4 The rationale for this (mostly successful) clinical decision is: higher dosages increase GC receptor saturation in a dose-dependent manner, which intensifies the therapeutically relevant genomic GC actions; and it is assumed that with increasing dosages additional and qualitatively different nonspecific nongenomic actions of GCs increasingly come into play.
Genomic Actions of Glucocorticoids
The important anti-inflammatory and immunomodulatory effects of GCs are mediated predominantly by genomic mechanisms (Figure 10B-1). Binding to cytosolic GC receptors (cGCR) ultimately induces (“transactivation”) or inhibits (“transrepression”) the synthesis of regulator proteins.4 GCs influence the transcription of approximately 1% of the entire genome.5 The lipophilic structure and low molecular mass allow GCs to pass easily through the cell membrane and to form an activated GC/cGCR complex. This receptor complex is then translocated into the nucleus, where it binds as a homodimer to consensus palindromic DNA sites, which are called GC-responsive elements (GREs)].6 Depending on the target gene, transcription is either activated (transactivation via positive GRE) or inhibited (negative GRE). In addition to these mechanisms, the interaction of activated cGCR monomers with transcription factors such as AP-1 (activator protein-1), NF-kB (nuclear factor-kappaB), and NF-AT (nuclear factor for activated T cells) is recognized as a further important genomic mechanism of GC action.7,8 Accordingly, although the GC/cGCR complex does not inhibit their synthesis it modulates the activity of these factors–which leads to inhibition of nuclear translocation and/or function of these transcription factors and hence to inhibition of the expression of many immunoregulatory and inflammatory factors (transrepression). There are indications that many adverse clinical effects are caused by the transactivation mechanism (i.e., induced synthesis of regulator proteins), whereas many important anti-inflammatory effects are mediated by transrepression (i.e., inhibited synthesis of regulator proteins). This differential molecular regulation provides the basis for current drug-discovery programs that aim at the development of dissociating cGCR ligands. These novel substances, also called selective GC receptor agonists (SEGRAs), are being developed in order to obtain drugs with high repression activities against inflammatory mediator production but lower transactivation activities than traditional GCs. At the moment, it cannot be reliably predicted whether SEGRAs will as “improved GCs” enter clinical medicine in the near future.4,9,10
Nongenomic Actions of Glucocorticoids
Some regulatory effects of GCs arise within a few seconds or minutes. Such observations cannot be explained by the previously mentioned genomic actions because of the time these require. Nongenomic mechanisms of action are thought to be responsible for these rapid effects. Three different nongenomic mechanisms have been proposed to explain rapid anti-inflammatory and immunosuppressive GC effects: nonspecific interactions of glucocorticoids with cellular membranes,3,4 nongenomic effects that are mediated by the cGCR,11,12 and specific interactions with membrane-bound GCR.10,13–15
Glucocorticoid Effects on Immune Cells
Based on the mechanisms mentioned previoulsy, GCs mediate fascinating anti-inflammatory and immunomodulatory effects when used therapeutically. There are many specific effects of the commonly used GC drugs: virtually all primary and secondary immune cells are more or less affected. A selection of the most important effects on the different cell types is outlined in Figure 10B-2.16
Suppression of inflammatory and immune reactions and treatment of cancers of the lymphoid system are among the major applications of glucocorticoids. As noted above, despite early assumptions that such ‘pharmacological’ effects had no physiological basis, it is now clear that they are as physiological as are the effects on glucose metabolism. For example, induction of adrenal insufficiency in experimental animals (by adrenalectomy or administration of the glucocorticoid antagonist RU486) enhances inflammatory and immune reactions, showing that these reactions are physiologically regulated by endogenous glucocorticoids. Studies by Sternberg and coworkers also strongly suggest that dysregulation of the HPA axis can result in autoimmunity.
Anti-inflammatory and immunosuppressive actions of glucocorticoids are now known to be closely related, affecting nearly all cells that participate in immunity and inflammation and sharing fundamental cellular and molecular mechanisms that are under glucocorticoid influence. Glucocorticoids dramatically alter the distribution of leukocytes, markedly decreasing blood counts of lymphocytes, monocytes, eosinophils and basophils within 1–3 h of glucocorticoid administration. Recent work has shown that changes in blood leukocyte distribution result from glucocorticoid interaction with the type II adrenal steroid receptor. While neutrophil counts rise in the blood, glucocorticoids decrease the accumulation of leukocytes at inflammatory sites. Glucocorticoids also kill lymphocytes, largely by the initiation of apoptosis, a striking effect that is applied in the treatment of lymphocytic leukemias and lymphomas.
Numerous reactions that are fundamental to immunity – antigen-induced T and B cell proliferation, early B cell differentiation, antigen presentation, NK activity, differentiation and activation of macrophages – are suppressed by glucocorticoids. Although some of these are probably direct effects on the target cell being measured, others certainly involve indirect effects resulting from glucocorticoid regulation of intermediary molecules. In the past 20 years, the ability to glucocorticoids to inhibit the production of various inflammatory enzymes and cytokines, by mechanisms such as those outlined above, began to be recognized. Table 1 contains a partial list of mediators which are obligatory components of immune and inflammatory reactions and whose production is inhibited by glucocorticoids. Glucocorticoids also inhibit some effects of these mediators, such as responses of lymphocytes to IL-2 and of eosinophils to IL-3, IL-5, GM-CSF and IFNγ. By blocking communication via cytokines, glucocorticoids cut off signals required for clonal expansion and differentiation of antigen-specific T and B cells, as well as signals which activate effector functions that participate in inflammatory reactions. It seems likely, therefore, that a principal mechanism through which glucocorticoids control immune and inflammatory reactions is by suppressing cytokines and other mediators.
Table 1. Glucocorticoid regulation of mediators involved in immunity and inflammation
The complexity of the interplay between glucocorticoids and inflammatory mediators is evidenced by the increased expression of certain cytokine receptors in response to glucocorticoids, and probably by altered expression of glucocorticoid receptors induced by some cytokines. How might such effects fit with the models presented in Figures 3 and 4? Basal levels of glucocorticoid, and possibly the surge which occurs early in an immune response, may initially enhance the actions of cytokines by increasing expression of cytokine receptors. As cytokine concentrations rise, they act on the HPA to stimulate even higher levels of glucocorticoids which restrain further cytokine production unless very strong inflammatory signals persist. Normally, elimination of the antigen and resolution of the inflammation allows cytokine production to cease so that both cytokines and glucocorticoids return to basal levels. However, sustained inflammation with continued high levels of cytokines can persist in spite of high levels of glucocorticoid. This outcome might result in part from cytokine-induced reduction in glucocorticoid receptor expression, a mechanism postulated by some to contribute to steroid-resistant asthma.
GC elevations inhibit activity in PVN CRF cells and pituitary corticotropes, first by membrane GR-mediated effects, then by GC-associated GR protein–protein interactions altering gene expression. Feedback ensures controlled neuroendocrine responses. Longer term feedback effects exist in both brain and pituitary (e.g., through GC–GR complexes interacting with a negative GRE on POMC in corticotropes). Chronic GCs diminish HPA axis outflow in proportion to exposure, provided no concurrent stress exists, making the axis unresponsive to new stressors and thus explaining the requirement for extra GC coverage during major surgery in patients on chronic GC therapy.
There is rapid inhibitory GC feedback on both CRF and ACTH secretion. In hypothalamic slices in vitro, GC alters neuronal activity, including CRF-synthesizing cells, within 3 min. GC stimulates endocannabinoid secretion, presynaptically inhibiting glutamate-stimulated miniature excitatory postsynaptic currents (mEPSCs) via endocannabinoid EC-1 receptors. GCs infused directly into neurons does not have this effect, and rapid GCs actions on pituitary ACTH secretion in vitro are not inhibited by exposure to protein or by RNA synthesis inhibitors, suggesting membrane-mediated feedback.
Glucocorticoids exert a wide range of physiological effects, including the induction of apoptosis in lymphocytes. The progression of glucocorticoid-induced apoptosis is a multi-component process requiring contributions from both genomic and cytoplasmic signaling events. There is significant evidence indicating that the transactivation activity of the glucocorticoid receptor is required for the initiation of glucocorticoid-induced apoptosis. However, the rapid cytoplasmic effects of glucocorticoids may also contribute to the glucocorticoid-induced apoptosis-signaling pathway. Endogenous glucocorticoids shape the T-cell repertoire through both the induction of apoptosis by neglect during thymocyte maturation and the antagonism of T-cell receptor (TCR)-induced apoptosis during positive selection. Owing to their ability to induce apoptosis in lymphocytes, synthetic glucocorticoids are widely used in the treatment of haematological malignancies. Glucocorticoid chemotherapy is limited, however, by the emergence of glucocorticoid resistance. The development of novel therapies designed to overcome glucocorticoid resistance will dramatically improve the efficacy of glucocorticoid therapy in the treatment of haematological malignancies.