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.