MECHANISMS OF NON-BIOLOGIC ANTIRHEUMATIC DRUGS REVIEWS Therapeutic glucocorticoids: mechanisms of actions in rheumatic diseases Rowan S. Hardy 1, Karim Raza2 and Mark S. Cooper 3* Abstract | Therapeutic glucocorticoids have been widely used in rheumatic diseases since they became available over 60 years ago. Despite the advent of more specific biologic therapies, a notable proportion of individuals with chronic rheumatic diseases continue to be treated with these drugs. Glucocorticoids are powerful, broad-spectrum anti- inflammatory agents, but their use is complicated by an equally broad range of adverse effects. The specific cellular mechanisms by which glucocorticoids have their therapeutic action have been difficult to identify, and attempts to develop more selective drugs on the basis of the action of glucocorticoids have proven difficult. The actions of glucocorticoids seem to be highly cell-type and context dependent. Despite emerging data on the effect of tissue-specific manipulation of glucocorticoid receptors in mouse models of inflammation, the cell types and intracellular targets of glucocorticoids in rheumatic diseases have not been fully identified. Although showing some signs of decline, the use of systemic glucocorticoids in rheumatology is likely to continue to be widespread, and careful consideration is required by rheumatologists to balance the beneficial effects and deleterious effects of these agents. The introduction of glucocorticoids and their notable of particular medical importance include osteoporosis effects in the treatment of patients with rheumatoid and fracture, glucose intolerance and diabetes, central arthritis (RA) led to the award of the Nobel Prize for obesity, muscle wasting, increased risk of infection, Physiology or Medicine in 1950 (REF.1). Subsequently, depression and cataracts6. The effect of glucocorticoids systemic glucocorticoid therapy has been employed in on bone depends on the dose and duration of therapy a range of rheumatic diseases. For many of these condi- but treatment durations beyond 3 months are associated tions, the evidence for glucocorticoid therapy remains with a 30% increase in overall fracture risk and at least a based on clinical experience rather than on rigorous doubled risk of vertebral fracture7. The risk of develop- clinical trials. Despite the introduction of biologic drugs, ing diabetes is doubled in patients with RA taking pred- which have a much greater specificity for compon ents nisolone doses of 7.5 mg or above5. Although adverse of the immune system than glucocorticoids, systemic effects on bone can be mitigated pharmacologically glucocorticoid therapy continues to be widely used2. with bisphosphonates or denosumab therapy 8, the effects In the general population, ~1% of individuals are on other tissues such as muscle wasting, skin thinning, 1 Institute of Metabolism treated with oral glucocorticoids on a long- term basis, obesity and increased risk of diabetes have no specific and Systems Research, 3,4 University of Birmingham, and this figure rises to around 3% in elderly individuals . treatment. Patient perceptions of such adverse effects Birmingham, UK. In individuals with RA, oral glucocorticoid usage contin- often differ from those of their treating clinician and are 2 9,10 2Institute of Inflammation ues to be widespread, although is potentially declining . important to consider . and Ageing, University For some conditions (such as systemic vasculitis, systemic Despite their widespread use over many decades, the of Birmingham, lupus erythematosus and polymyalgia rheumatica), the underlying anti- inflammatory mechanisms of gluco- Birmingham, UK. use of glucocorticoids for long periods of time remains corticoids remain unclear. Many cell types and cellu- 3 ANZAC Research Institute, an important part of current treatment approaches. lar pathways have been proposed as important targets. University of Sydney, Sydney, Australia. The adverse effects of prolonged glucocorticoid Experimental evidence suggests that there is likely a 5 *e- mail: mark.cooper@ therapy are well established and extremely common . diversity of cell types and pathways involved, and that sydney.edu.au Glucocorticoids have effects on almost all tissues and these targets likely differ between different disease con- https://doi.org/10.1038/ bodily systems (the selected effects of glucocorticoids are texts. An improved understanding of these targets in s41584-020-0371-y represented in Supplementary Figure 1). Adverse effects specific disease states opens up the potential to design NATURE REVIEWS | RHEUMATOLOGY VOLUME 16 | MARCH 2020 | 133 REVIEWS Key points transported to the nucleus after binding of the recep- tor by the glucocorticoid. The molecular actions arising • Therapeutic glucocorticoids are powerful, broad- spectrum anti-inflammatory from the glucocorticoid-bound glucocorticoid receptor agents that are limited by a wide range of adverse effects. are discussed in a later section. • The specific mechanisms of action by which glucocorticoids mediate anti- inflammatory The mineralocorticoid receptor is expressed pri- effects in rheumatic diseases are still unclear, hindering the development of novel marily in cells that regulate salt and water balance, therapeutic agents. such as the distal tubule of the kidney, the salivary • Approaches to the study of glucocorticoid actions have been complicated by the and sweat glands and the colonic epithelium. Even widespread use of animal tissues and transformed cell lines rather than human though gluco corticoids such as cortisol and predniso- primary cells. lone have an affinity for the mineralocorticoid recep- • The development of novel glucocorticoids that ‘dissociate’ molecular transrepression tor, the inter action between these glucocorticoids and from transactivation have proven difficult; however, one such dissociated glucocorticoid agonist is undergoing clinical trials in patients with inflammatory the mineralocorticoid receptor is prevented by the arthritis. presence of an enzyme (11β-hydroxysteroid dehydro- • The use of genetically modified mice with altered glucocorticoid sensitivity in specific genase type 2 (11βHSD2)); this enzyme inactivates tissues and/or transcriptomic studies using primary human cells are promising these gluco corticoids in mineralocorticoid- sensitive 14 approaches for defining cellular and molecular glucocorticoid targets. cells . Glucocorticoids such as dexamethasone and triamcinolone do not bind the mineralocorticoid receptor and thus have no mineralocorticoid activity. novel therapeutics that retain anti- inflammatory effects with a reduced risk of adverse consequences. Pharmacokinetics In this Review, we summarize the current under- A fundamental structural property of therapeutic glu- standing of the basis by which glucocorticoids have cocorticoids is that they can pass through biological therapeutic effects in inflammatory, and in particular membranes to access intracellular receptors (Fig. 2). rheumatic, diseases. We consider the pharmacological Glucocorticoids such as prednisone and prednisolone properties that enable glucocorticoids to have useful are efficiently absorbed through the gastrointestinal effects in a wide range of conditions and the probable tract. Although poorly soluble in water due to their lipo- cellular targets of these actions. We also consider the philic nature, glucocorticoids can be carried effectively molecular mechanisms underlying the adverse effects of in the circulation through their association with plasma glucocorticoids and assess the prospects for developing proteins (primarily corticosteroid-binding globulin and novel therapeutics that retain beneficial properties with albumin). Orally or intravenously administered gluco- reduced risks of adverse effects. corticoids can thus penetrate most tissues. Coupled with the almost universal distribution of glucocorticoid Glucocorticoids and their receptors receptors within tissues, this high degree of penetration Cortisol (referred to as hydrocortisone when used as means that glucocorticoid therapy can target cells that a therapeutic) is the main endogenous glucocorticoid mediate inflammation at a systemic level. This high bio- in humans. Cortisol secretion is essential to life11. This availability, however, comes at the price of considerable steroid hormone is released in a pronounced circadian ‘off-target’ exposure of tissues unrelated to the condition rhythm (high in the morning before waking and very being treated. Some therapeutic glucocorticoids, such low around midnight), and its synthesis is considerably as cortisone and prednisone, lack intrinsic glucocor- upregulated during states of stress. Cortisol is synthesized ticoid receptor binding activity, but when given orally in the adrenal cortex from cholesterol and retains the are converted to their active counterparts, cortisol and cyclopentanoperhydrophenanthrene ‘steroid’ backbone prednisolone, by 11βHSD1, an enzyme that is highly structure. The synthetic glucocorticoids most commonly expressed in the liver (Fig. 2). Expression of 11βHSD1 in used to treat systemic inflammation in rheumatology various stromal and immune cells can also amplify the (prednisolone, methylprednisolone and dexametha- actions of these glucocorticoids locally through conver- sone) are very similar in structure to cortisol, with only sion of these glucocorticoids from their inactive to their relatively modest modifications (Fig. 1). These changes active forms15,16. variously reduce