More on the myths and perceived magic of corticosteroids

Clinical medicine is rife with reflex practices based on beliefs mired in our sometimes limited understanding of pathophysiology in the absence of relevant data. It often is difficult to evaluate the appropriateness of these practices with rigorously conducted clinical trials. Some we justify by saying that a large randomized study is not necessary to demonstrate that parachutes are effective protection when jumping out of a plane. But this clearly is not a reasonable or accurate conceptual justification for most of our treatment and diagnostic behaviors, even those that may seemingly be supported by experience or retrospective observational studies. I previously commented on our use of corticosteroids in the setting of sepsis.¹ In this issue of the Journal, Timberlake et al² discuss a different use of corticosteroids—preventing infusion reactions to intravenous diagnostic and therapeutic agents.

The concept that corticosteroids can ameliorate or partially prevent reactions provoked by infusions, as well as treat allergic reactions that are spontaneous or environmentally triggered, is widely accepted. This includes the treatment of anaphylaxis. However, there is scant evidence for the efficacy of corticosteroids in treating anaphylaxis, and guidelines suggest that corticosteroids should not generally be prescribed for this purpose.³ I looked through our algorithmic infusion protocols for the suggested administration of medications to prevent or treat infusion hypersensitivity reactions. Many therapy protocols included pretreatment corticosteroids for patients getting an initial dose as well as those receiving ongoing maintenance therapy (even those with no prior infusion reactions), and almost all the protocols included the option to reflexively administer a corticosteroid as a component of treatment for hypersensitivity reactions. I realize that corticosteroids being listed as an option does not mean that every patient with an infusion reaction will be treated with them, but many with significant reactions will receive them.

As I delved into this topic, I was struck by the enormous evidence gap regarding the therapeutic efficacy of corticosteroids to prevent infusion reactions. I was also intrigued by the frequently described pattern of infusion reactions occurring mainly in patients receiving their initial dose of intravenous monoclonal antibodies and some other biologics.

In terms of prophylactic efficacy, a seminal observation regarding hypersensitivity reactions to high-osmolar radiocontrast material was that for any benefit to be observed, the corticosteroid needed to be administered about 12 hours before the infusion of contrast media^4,5; corticosteroid pretreatment given 2 hours or less before the infusion was not effective. Surprisingly, there are minimal data on the prophylactic efficacy of corticosteroid pretreatment for patients at high risk for recurrence of these infusion reactions. It is not certain whether this requirement for administration of corticosteroids well in advance of the infusion, providing time for the steroid to exert its known genomic effects, applies to other infused therapeutics. Nonetheless, many protocols include the administration of corticosteroids around the time of the infusion, without robust supportive data for the efficacy of this practice.

Infusion reactions to some medications are characterized as occurring primarily after the first infusion, with a diminution in the likelihood of recurrence with subsequent infusions. Rituximab, a monoclonal antibody targeting CD20-bearing lymphocytes, is a prime example. This is not an expected result from reactions driven by anti-drug antibodies, and may instead reflect the release of cytokines from injured or dying immune cells. It is not at all clear that corticosteroid pretreatment needs to be provided with each ongoing maintenance treatment in patients with lymphoma who have not had infusion reactions,⁶ although pretreatment seemingly is fairly common practice. There are inadequate data to directly guide decision-making in patients receiving rituximab as treatment for their autoimmune disease,⁷ but it would seem that limiting pretreatment corticosteroids in lower-risk patients receiving maintenance therapy might be another way to limit chronic corticosteroid side effects. The ongoing inclusion of corticosteroid pretreatment in other maintenance therapeutic protocols of drugs not designed to induce targeted cell death, such as pegloticase (a pegylated uricase used in the treatment of refractory gout), should also be reassessed.

Timberlake et al² discuss the specific benefit of corticosteroid pretreatment for several discrete classes of drugs and provide a useful reminder to think about the relative utility of routine corticosteroid pretreatment based on the specific agent being infused.

As we enter 2026, the Journal’s 95th year of publication, on behalf of our entire editorial team, I offer our sincere thanks to our authors and peer reviewers. And to you, our readers, I offer our best wishes and hopes for a healthy, happy, and peaceful New Year.

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