Team: Cortisone, aka “Rheum on the Rocks”

Region: Origin Story

Base article: Hench PS, Kendall EC, et. al. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin. 1949;24(8):181-197.

Authors: University of Colorado Rheumatology Fellowship Program. Smarika Sapkota, MD, second year rheumatology fellow, David DeFrancisco, MD, first year rheumatology fellow, Jason Kolfenbach, MD, Associate Professor of Medicine.

Team Overview

Philip Hench and colleagues published their landmark article in 1949, during an era in which knowledge regarding the pathologic underpinnings of rheumatoid arthritis (RA) was limited, as were treatment options. Patients at that time were treated with aspirin (distributed by Bayer in 1899)2, or much less commonly gold or sulfonamide compounds (1930s)3, often with limited success. The initial use of sulfonamide compounds such as sulfasalazine, as well as medications such as d-penicillamine (1950s), reflected a prevailing hypothesis that RA was a microbial-driven disease.

In this landmark study, Hench and colleagues demonstrated remarkable clinical and laboratory improvements in RA disease control through administration of their ‘Compound E’ (17-hydroxy-11-dehydrocorticosterone) to 14 patients with severe RA. This study was critical to the field of rheumatology not only for the discovery of an effective therapeutic agent (cortisone), but also because it supported a biochemical basis of disease rather than a microbial origin.

Prior to the publication of this study, Hench had studied the beneficial effects of pregnancy and jaundice on RA. The improved disease activity that he observed in these settings was a novel finding, as RA was previously thought to be an irreversible disease. Based on his observations, he sought to find a common biochemical denominator between pregnancy and jaundice that could lead to a potential therapeutic intervention for RA. After a series of trial-and-error experiments, the team settled on an adrenal hormone as the most likely ‘anti-rheumatic substance X’, and on September 21, 1948, they began treating their first patient with Compound E.

This study describes the subjective and objective responses of 14 patients following treatment with Compound E. Improvement was noted in muscle and joint pain, functional status, appetite, strength, and overall sense of well-being (including the first description of steroid-associated ‘euphoria’). In addition, reductions in ESR and serum gammaglobulin were reported, as well as improvement in disease-associated anemia. The biologic effect of Compound E was further supported by studies of drug withdrawal and subsequent re-institution upon disease flare.

Impact on Rheumatology

This landmark study provided the first evidence that corticosteroids could significantly improve the lives of patients suffering from RA, and its results suggested an alternative to the microbial theory of disease pathogenesis. This latter discovery shaped research in the decades to follow, helping to steer the field away from viewing RA as primarily the result of an infectious agent and shifting the focus toward therapeutics without anti-microbial properties. The experiments described in this study also relied upon collaboration with industry partners (Merck and Co.), a foreshadowing of the academic-industry relationship that drives many drug discoveries of today.

Following the improvement seen in patients with RA, Hench and colleagues then began to administer Compound E to lupus patients, with ‘encouraging results’, and describe a patient with myasthenia gravis who improved following treatment with ACTH. These point to the widespread applicability of corticosteroids in inflammatory/autoimmune disease.

Chances in the Tournament

Do we love this study? Let us count the ways: the discovery of the therapeutic potential of steroids, evidence of a biochemical basis of RA, initial descriptions of steroid-related side effects, and application to other diseases such as lupus and myasthenia gravis. Oh, and yes, the authors were awarded the Nobel Prize (the following year!) as a result of their decades long work in this area.

While we believe this study is a clear favorite to win the tournament, it may also be viewed by some readers as a ‘blue-blood’ that needs to step aside and make way for new therapies. Just as many fans have become tired of seeing Duke basketball play in the past 25 NCAA tournaments, or SEC football teams annually winning the championship game, some may feel that prednisone has already had its day in the sun.

It may also be tempting to overlook this study due to the side effects associated with corticosteroids, as well as numerous studies investigating the ability to reduce our dependence on them4-6. Even so, it’s important to recognize that all medications have side effects, and as with any drug, medication risk can be mitigated by a cautious, conscientious prescriber, and balanced against the potential benefit. With this said, let’s recognize the many positives this precious gift provides to our patients with rheumatic disease and give credit where it’s due. So, the next time you are consulted on a patient with diffuse alveolar hemorrhage and a pulmonary-renal syndrome in the ICU, think of the value of corticosteroids, and the impact their discovery has had on the field of medicine.

Next scouting report: Origin of RA

Back to the full list of scouting reports.


  1. Hench PS, Kendall EC, et. al. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin. 1949;24(8):181-197.
  2. Sneader W. The discovery of aspirin: a reappraisal. BMJ. 2000 Dec 23; 321(7276): 1591–1594.
  3. Svartz N. The treatment of rheumatic polyarthritis with acid azo compounds. Rheumatism. 1948;4(1):180-185. Compounds
  4. Stone JH, et. al. NEJM. 2017;377:317-28.
  5. Jayne DR, et. al. NEJM. 2021;384:599-609
  6. Walsh M, et. al. NEJM. 2020;382:622-31.

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