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• Hench PS. The analgesic effect of hepatitis and jaundice in chronic arthritis, fibrositis, and sciatic pain, Ann Internal Med. 1934:7:1278-1294.
• Hench PS. The ameliorating effect of pregnancy on chronic atrophic (infectious, rheumatoid) arthritis, fibrositis, and intermittent hydrarthrosis, Proc Staff Meetings Mayo Clinic 1938;13:161-167.
• Hench PS, Kendall EC, Slocumb CH, Polley HF. The effect of a hormone of the adrenal cortex (17-hydroxy-II-dehydrocorticosterone: compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis (Preliminary Report). Proc Staff Meetings Mayo Clinic 1949;24:181-197; more officially and international: Ann Rheum Dis. 1949;8:97-104.

Philip Showalter Hench (1896-1965) was an American rheumatologist. Together with his colleague Edward C Kendall and the Swiss chemist Tadeus Reichstein, he was awarded the Nobel Prize for Medicine in the year 1950 for the discoveries on steroid hormones and their favorable effects in rheumatoid arthritis (RA). Philip Hench received his MD degree from the University of Pittsburgh in 1922 and started his career in 1923 at the Mayo Clinic, Rochester, Minnesota.

Already in the late 1920s, he observed the extremely favorable effects of jaundice in a patient with RA. At the time, this was a great surprise because RA remission was a medical curiosity. Between 1929 and 1934, he collected data of 16 patients with RA who developed jaundice that ameliorated the crippling disease (1). Today we know that in the bile, some biliary acids with the typical steroid hormone structure can have anti-inflammatory activities (2). However, many therapeutic approaches with bile or compound thereof – he expected the healing “substance X” in the bile – were not successful.

At the same time, he observed the ameliorating effect of pregnancy in women with RA, and he speculated on a “common denominator substance X” favorable in jaundice and pregnancy (3). He wrote: “It does not seem illogical to suppose that the agents responsible for both these phenomena are closely related, perhaps identical, and if the agent were a chemical substance, it would appear that it is neither bilirubin nor a strictly female sex hormone.”

During the hunt for “substance X”, Philip Hench also recognized that other inflammatory diseases like psoriasis arthritis, asthma, hay fever, Addison’s disease, and even migraine were sometimes relieved during pregnancy and/or jaundice. Substance X was unspecific and bisexual.

In the early 1940s he started a collaboration with Edward Kendall “in a laboratory [at Mayo Clinic] a few yards away”. Edward Kendall and colleagues –biochemists – already isolated several adrenal steroid hormones in the late 1930 (4), but administration of them lasted years because the substance was difficult to isolate from extracts. In the year 1948, in a collaboration of Edward Kendall and the American company of Merck & Co., Inc., enough compound E was available to treat a woman “badly crippled with RA” (5). More patients followed with highly favorable results (figure) (5). The similar effects of adrenocor-ticotropic hormone (ACTH) were correctly linked to the ACTH-induced secretion of adrenal glucocorticoids. This was the breakthrough! In Switzerland, concurrently, Tadeus Reichstein also discovered the different adrenal hormones.

Fig 1. Influence of compound E (17-hydroxy-11-dehydrocorticosterone) on erythrocyte sedimentation rate of the first 14 patients with RA treated. Graph created by the blogger combining the tabular data published in Hench PS et al. (1949).

Today, we well know that therapeutic glucocorticoids ameliorate inflammation in autoimmune diseases and other inflammatory diseases. The anti-inflammatory effects of glucocorticoids stood the test of time. However, we also know that glucocorticoids must be administered at low doses up to 5 mg prednisolone per day to avoid side effects (6-8).

The journal Neuroimmunomodulation published several papers on glucocorticoids (6-10). In 2015, a special issue appeared in the journal.

References

1. Hench PS. The analgesic effect of hepatitis and jaundice in chronic arthritis, fibrositis, and sciatic pain, Ann.Internal Med. 1934:7:1278-1294.
2. Poupon R. Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action. Clin Res Hepatol Gastroenterol. 2012;36(Suppl 1):S3-S12.
3. Hench PS. The ameliorating effect of pregnancy on chronic atrophic (infectious, rheumatoid) arthritis, fibrositis, and intermittent hydrarthrosis, Proc. Staff Meetings Mayo Clinic 1938;13:161-167.
4. Mason HL, Hoehn WM, Kendal EC. Chemical studies of the suprarenal cortex: IV. Structures of compounds C, D, E, F, AND G. J Biol Chem. 1938;124:459-474.
5. Hench PS, Kendall EC, Slocumb CH, Polley HF. The effect of a hormone of the adrenal cortex (17-hydroxy-II-dehydrocorticosterone: compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis (Preliminary Report). Proc. Staff Meetings Mayo Clinic 1949;24:181-197; Ann Rheum Dis. 1949;8:97-104.
6. Pincus T, Sokka T, Cutolo M. The past versus the present, 1980-2004: reduction of mean initial low-dose, long-term glucocorticoid therapy in rheumatoid arthritis from 10.3 to 3.6 mg/day, con-comitant with early methotrexate, with long-term effectiveness and safety of less than 5 mg/day. Neuroimmunomodulation. 2015;22:89-103.
7. Hwang YG, Saag K. The safety of low-dose glucocorticoids in rheumatic diseases: results from observational studies. Neuroimmunomodulation. 2015;22:72-82.
8. Santiago T, da Silva JA. Safety of glucocorticoids in rheumatoid arthritis: evidence from recent clinical trials. Neuroimmunomodulation. 2015;22:57-65.
9. Cruz-Topete D, Cidlowski JA. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation. 2015;22:20-32.
10. Silverman MN, Sternberg EM. Neuroendocrine-immune interactions in rheumatoid arthritis: mechanisms of glucocorticoid resistance. Neuroimmunomodulation. 2008;15:19-28.

Special Topic Issue: Stress, the Stress System and the Role of Glucocorticoids, Neuroimmunomodulation, Volume 22, Issue 1-2 (September 2014).