Corticosteroids and erythropoeitin-receptor agonists

The excellent meta-analysis by Ryan Zarychanski and associates demonstrated that the use of erythropoietin-receptor agonists in critically ill patients does not improve clinically important outcomes.¹ Interestingly, the potential drug interaction with corticosteroids was not considered in the study.¹ Corticosteroids are now widely administered in critical care settings for adrenal supplementation and attenuation of the inflammatory and immune response.² It is probable that the lack of therapeutic effect for erythropoietin-receptor agonists in the trials conducted thus far could be explained by the fact that a substantial number of the participants would also have been receiving corticosteroids that interfered with or blunted the efficacy of the erythropoietin-receptor agonists.

There is experimental and molecular evidence of the negative effects of corticosteroids on the efficacy of erythropoietin-receptor agonists. An experimental study of spinal cord injury showed that coadministration of the corticosteroid methylprednisolone sodium succinate antagonized the protective effects of erythropoietin-receptor agonists, even though the erythropoietin receptor was upregulated normally after injury.³

Cellular signalling pathways for the activation of the erythropoietin receptor may further explain why corticosteroids blunt the actions of erythropoietin-receptor agonists. JUN N-terminal kinase and p38 (members of the mitogen-activated protein kinase family of serine-threonine kinases) are important in erythropoietin signalling.⁴ These pathways are activated as a result of cellular stress but may also play a role in the proliferation, survival or differentiation of many cell types induced by growth factors. Corticosteroids have been shown to induce the rapid and sustained expression of dual-specificity phosphatase 1 (also known as mitogen-activated protein kinase phosphatase 1), which is a particularly effective inhibitor of the JUN N-terminal kinase and p38 mitogen-activated protein kinase signalling pathways.⁵ Thus, the beneficial effects of erythropoietin-receptor agonists are mediated by the JUN N-terminal kinase and p38 cellular signalling pathways, whereas the anticytokine effects of corticosteroids are mediated by inhibition of these 2 pathways.

A detailed subgroup reanalysis of the patients in the meta-analysis who were receiving both corticosteroids and erythropoietin-receptor agonists is warranted. It is likely that between 25% and 30% of the participants received a corticosteroid. Experimental data suggest that corticosteroids and erythropoietin-receptor agonists should not be coadministered to patients because the therapeutic effects of the erythropoietin-receptor agonists are likely to be blunted.