When I teach trainees about the treatment of rheumatoid arthritis (RA), I always start with questions about glucocorticoids, asking about the first therapeutic use of these agents. Addison’s disease and Cushing syndrome are the usual answers I receive, but I tell the trainees it was another disease.
I then give a hint, “Clinical observations on patients with RA provided a decisive clue,” and I ask, “What could happen in RA to suggest a role of hormones?” If I don’t receive an immediate response, I ask, “Who gets RA most often, men or women? What can happen to a woman to improve RA?”—sometimes adding, “something that can’t happen to a man?”
Eventually, the trainee realizes I am referring to pregnancy. Finished with the Socratic method, I then describe research at the Mayo Clinic on compound E (i.e., cortisone) to treat RA based on the prescient observation that women with RA can have remissions during pregnancy.1 After noting the Nobel Prize presented to Kendall, Reichstein and Hench for the discovery of glucocorticoids, I then discuss how this group of drugs is now used by essentially every medical specialty in an extraordinary variety of formulations (e.g., oral, parenteral, topical, inhalational, etc.) and various indications. Further, I explain that glucocorticoids are given in doses ranging over three orders of magnitude. For rheumatologists, these doses extend from 1 to 2 mgs of prednisone a day for chronic RA—a “whiff” of steroids as we used to say—to a 1 g pulse of methylpredisolone (Solu-Medrol) for rapidly progressive glomerulonephritis in systemic lupus or vasculitis.
The meaning of low-, moderate- and high-dose glucocorticoids remains vague and should probably include categories for very low and very high. Nevertheless, I find this dose range remarkable because it far exceeds that of any other drug. I often wonder what happens at 1 g of methylprednisolone that does not happen at 1 mg of prednisone. Interestingly, a study of patients treated with tocilizumab indicated that, for some patients, a few milligrams of prednisone provides better disease control than a complete taper, even though blocking interleukin (IL) 6 signaling would seem sufficient to control inflammation.2 What does a whiff of prednisone do that a potent biologic can’t?
When I began my career as a rheumatologist, the array of disease-modifying anti-rheumatic drugs (DMARDs) was limited and even those in common use were viewed with skepticism. Although the efficacy of gold salts was established in the Empire Rheumatism Council Trial, many physicians simply did not believe these agents worked.3 Certainly, when methotrexate came along, this group of SAARDs (slow- acting anti-rheumatic drugs, so named to contrast with the more rapid-onset methotrexate) was rapidly abandoned. The treatment pyramid either disappeared or was turned upside down and sideways into another geometry.