Based on this assumption, they began treating a number of patients with a variety of adrenal and bile salt extracts, but they failed to achieve any breakthroughs. In January 1941, they decided to administer compound E, or 17-hydroxy 11-dehydrocorticosterone, to patients with RA. This compound increased the resistance of animals against reactions to typhoid vaccine, and it had been observed that these vaccines could induce striking but transient remissions of RA.
The only problem was they lacked a sufficient supply to administer to patients. So, as Hench noted, “I recorded this idea in my pocketbook.” It took seven years for the actual experiment to take place. In 1948, the first patient, who had longstanding refractory RA, was treated with 100 mg of the compound daily, and by the third day she had dramatically improved. The rest is history—Hench and Kendall shared the 1950 Nobel Prize with Tad Reichstein, an organic chemist in Basel who had simultaneously described the chemical composition of cortisone. Perhaps equally amazing to this story is the speed with which the Nobel Prize was awarded. To be precise, the ceremony in Stockholm occurred less than 27 months after the first patient was treated in Rochester and 19 months after the authors had presented their data to a public forum for the first time.
Modern RA Treatment
Flash forward to the late 1970s. Rheumatologists still believed in pyramids. We were stuck in the era of treating RA damage after the fact. There were no effective strategies to prevent damage. If there was a concept diametrically opposite to the current paradigm of treating to target, then this was it and the ’70s was its heyday. A rheumatology mentor of mine described his role then as being similar to the relief pitcher of the baseball team trailing by five runs who is brought in to keep the score respectable (European and Canadian readers can replace “pitcher” with football and hockey goaltender, respectively!).
It took methotrexate to shake us out of our complacency. Its precursor, aminopterin, had been regarded as a potent inhibitor of connective tissue proliferation. This effect was thought to mimic the pharmacologic effect of the newly discovered corticosteroids. Interestingly, Richard Gubner, a cardiologist at Kings County Hospital in Brooklyn, N.Y., first reported the use of aminopterin in patients with RA or psoriatic arthritis in 1951. Despite its potential for use in the rheumatology population, the next generation compound, methotrexate, did not gain widespread use for another thirty years. Four randomized clinical trials published in 1984–85 demonstrated the beneficial effects of methotrexate when administered to patients with established disease who had failed to respond to other therapies in use at the time, such as gold salts and D-penicillamine.
