Elsevier

The Lancet

Volume 373, Issue 9678, 30 May–5 June 2009, Pages 1905-1917
The Lancet

Review
Glucocorticoid resistance in inflammatory diseases

https://doi.org/10.1016/S0140-6736(09)60326-3Get rights and content

Summary

Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases—including chronic obstructive pulmonary disease and acute respiratory distress syndrome; it is also an issue for some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux. Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor κB, although these drugs are all likely to have major side-effects. An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples of this approach are inhibition of p38 MAP kinase, use of vitamin D to restore interleukin-10 response, activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-δ inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein.

Introduction

Glucocorticosteroids (glucocorticoids; also known as corticosteroids or steroids) are the most effective anti-inflammatory treatments available for many inflammatory and immune diseases, including asthma, rheumatoid arthritis, inflammatory bowel disease, and autoimmune diseases. However, a few patients with these diseases show a poor or absent response even to high doses of glucocorticoids. Other inflammatory diseases, such as chronic obstructive pulmonary disease (COPD), interstitial pulmonary fibrosis, acute respiratory distress syndrome, and cystic fibrosis, seem to be largely glucocorticoid resistant. Since chronic inflammatory diseases are widespread and their prevalence is rising, glucocorticoid resistance or insensitivity represents an important barrier to effective treatment and accounts for substantial health-care spending. We discuss resistance to the anti-inflammatory effects of corticosteroids and the recent identification of several molecular mechanisms of glucocorticoid resistance that might be amenable to new therapeutic approaches.

Section snippets

Glucocorticoid-resistant and insensitive diseases

Although most glucocorticoid resistance studies have focused on asthma, evidence is emerging that similar glucocorticoid resistance is found in many other allergic and chronic inflammatory diseases. The prevalence of glucocorticoid resistance is difficult to measure because of differences in how it is defined and variations over time.

How glucocorticoids suppress inflammation

There have been major advances in the understanding of molecular mechanisms by which glucocorticoids suppress inflammation,40, 41 mainly as a result of research into the proinflammatory and anti-inflammatory genes that they activate and suppress.

Molecular mechanisms of glucocorticoid resistance

Several distinct molecular mechanisms that contribute to decreased anti-inflammatory effects of glucocorticoids have now been identified; there is, then, heterogeneity of mechanisms even within a single disease (panel 1 and figure 4). Similar molecular mechanisms have been identified in different inflammatory diseases, suggesting that common therapeutic approaches might be developed in the future.

Therapeutic implications

There are several therapeutic strategies for management of glucocorticoid-resistant diseases, but the most important general approaches are to use alternative anti-inflammatory (“steroid sparing”) treatments or to reverse the molecular mechanisms of glucocorticoid resistance, if these are known (panel 2). Selective glucocorticoid receptor agonists (SEGRAs; or dissociated steroids) are more effective in transrepression than in transactivation and therefore have few side-effects. However, it is

Reversing glucocorticoid resistance

The most attractive option for treating glucocorticoid resistance is to reverse its cause. For example, this could be achieved by smoking cessation in asthmatic patients who smoke.118 In the future, reversal might be possible for some patients with glucocorticoid-resistant asthma by treatment with p38 MAP kinase inhibitors, JNK inhibitors, and vitamin D3.60, 83, 96 A monoclonal antibody to interleukin-2 receptor (anti-CD25, basiliximab) was found to be clinically effective in patients with

Conclusions

Glucocorticoid resistance is important in several common inflammatory diseases and complicates their clinical management. Many different molecular mechanisms of glucocorticoid resistance have now been elucidated, which might lead to new therapeutic strategies in the future, including the prospect of reversing glucocorticoid resistance.

Search strategy and selection criteria

We searched PubMed for relevant reviews and original articles published during the past 10 years. Search terms were “steroid”, “glucocorticoid”, or “corticosteroid”, and “resistance”. We combined these terms with “asthma”, “COPD”, “ARDS”, “cystic fibrosis”, “rheumatoid arthritis”, “inflammatory bowel disease”, “ulcerative colitis”, Crohn's disease”, and “interstitial pulmonary fibrosis”. Owing to space limitations, we cite recent review articles where possible and do not discuss steroid

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