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Therapeutic glucocorticoids: mechanisms of actions in rheumatic diseases

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.

Key points

  • Therapeutic glucocorticoids are powerful, broad-spectrum anti-inflammatory agents that are limited by a wide range of adverse effects.

  • The specific mechanisms of action by which glucocorticoids mediate anti-inflammatory effects in rheumatic diseases are still unclear, hindering the development of novel therapeutic agents.

  • Approaches to the study of glucocorticoid actions have been complicated by the widespread use of animal tissues and transformed cell lines rather than human primary cells.

  • The development of novel glucocorticoids that ‘dissociate’ molecular transrepression from transactivation have proven difficult; however, one such dissociated glucocorticoid agonist is undergoing clinical trials in patients with inflammatory arthritis.

  • The use of genetically modified mice with altered glucocorticoid sensitivity in specific tissues and/or transcriptomic studies using primary human cells are promising approaches for defining cellular and molecular glucocorticoid targets.

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Fig. 1: Natural and synthetic glucocorticoids.
Fig. 2: Systemic and local metabolism and inactivation of circulating glucocorticoids.
Fig. 3: Glucocorticoid receptors.
Fig. 4: Molecular mechanisms of glucocorticoid receptor signalling.
Fig. 5: The deleterious actions of glucocorticoids in muscle and bone.

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The authors acknowledge the support of the Versus Arthritis Research into Inflammatory Arthritis Centre collaboration at the University of Birmingham.

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Correspondence to Mark S. Cooper.

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Nature Reviews Rheumatology thanks J. Tuckermann, L. Franco and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Hardy, R.S., Raza, K. & Cooper, M.S. Therapeutic glucocorticoids: mechanisms of actions in rheumatic diseases. Nat Rev Rheumatol 16, 133–144 (2020). https://doi.org/10.1038/s41584-020-0371-y

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