The 70th Anniversary of Glucocorticoids in Rheumatic Diseases

The Second Youth of an Old Friend

Yannick Palmowski; Thomas Buttgereit; Frank Buttgereit

Disclosures

Rheumatology. 2019;58(4):580-587. 

In This Article

Historical Perspective and Current Importance of GC

When the first patient with RA was treated with GCs in 1948, the effect was so overwhelming that it marked the beginning of a new era—not only in the treatment of RA, but for the whole field of rheumatology and even medicine in general. The impact of this event was so immense that authors of a previous review captured it by dividing the history of rheumatology into BC and AC (before cortisone and after cortisone).[6] RA evolved from an almost untreatable and often debilitating disease to something physicians were able to treat for the first time in medical history. And still, this date only marked the last step after many years of intense research.

The first steps date back to the beginning of the 20th century, when several researchers like George W. Crile and Walter Cannon had started to investigate the influence of stress on the human body and its possible role in the aetiology of chronic diseases.[7–11] However, early research on stress focused mainly on the acute component triggered by adrenaline and noradrenaline from the adrenal medulla.[12] In the 1930s, Hans Selye added the element of chronicity and started to shift the focus towards the steroid hormones from the adrenal cortex.[12] In his laboratory rats, he observed a number of seemingly unconnected reactions—including enlargement of the adrenal glands, atrophy of the thymus and the occurrence of gastroduodenal ulcers—that simultaneously took place in response to completely different stimuli. Possible triggers ranged from injections with extracts from organs (e.g. ovaries and placenta) to sudden temperature changes.[13,14] This reminded him of a similar unspecific reaction he had observed in human patients. Patients suffering from completely different diseases often shared common particularities, which he summarized as looking sick. He suspected this looking sick to be a result of the same characteristic yet unspecific response to adverse conditions he had seen in his laboratory subjects and called it the general adaption syndrome.[15] In further experiments he observed that the reaction could be completely prevented by removing the adrenals, which was in perfect accordance with his observation of enlarged adrenal glands as part of the response.[14] Although the theory of the general adaptation syndrome itself has been largely discarded nowadays, back then it helped to fertilize the research on stress and the mediating hormones.[12]

Around the same time that Selye developed his hypothesis, researchers from the Mayo Clinic discovered that an extract from the cortex of bovine adrenals could keep alive adrenalectomized laboratory animals and alleviate symptoms in patients suffering from Addison's disease, a disease characterized by an atrophy of the adrenal glands. However, the extraction from bovine adrenals could not deliver sufficient quantities for widespread use as a drug. In order to produce it on an industrial scale, the active agent needed to be isolated. Finally, Edward Calvin Kendall succeeded in isolating four physiologically active substances from the adrenal cortex, which he named compounds A, B, E and F.[16] Of these, compound E (now known as cortisone) demonstrated the best effectiveness in prolonging the life of adrenalectomized subjects and thereby qualified as the number one candidate for further research.[17]

During the following years, research on the newly discovered stress hormones was boosted by the outbreak of World War II. According to rumours, Germany was buying large quantities of bovine adrenal glands to make their pilots more resistant to hypoxia at high altitudes and to treat septic shock in wounded soldiers.[13,16,18] Consequently, great efforts were undertaken by the Allies to investigate the use of adrenal hormones for these purposes and to establish a method for their production on an industrial scale. In December 1944, these efforts bore fruit as industrial chemist Lewis Sarett, at Merck, succeeded in synthesizing a small amount of compound E.[18] However, at that time the breakthrough seemed to come too late: not only was the war almost over, the rumours about the use of GCs in the Luftwaffehad already been disproven. With a synthetic pathway for their production finally discovered, the general interest in GCs had largely vanished.

Among the last groups still pursuing their research on GCs was one at the Mayo Clinic. There, Kendall's long-time collaborator Philip Showalter Hench[19] had observed a seemingly miraculous alleviation of symptoms in several patients with RA from jaundice and pregnancy and hypothesized elevated corticosteroid levels to be the reason.[20] In addition, he suspected a latent hypoadrenia in patients with RA, as they often showed symptoms commonly found in Addison's disease, such as fatigue, hypotension, an asthenic habitus and low blood glucose.[17,20,21] Interestingly, this idea might still turn out to have clinical relevance.[22,23] Consequently, he decided to give compound E a try and administered the first dose to a patient with RA on 21 September 1948—a day that marks the beginning of a new era in the history of medicine.[17,24,25] The effect was spectacular. The patient, a 29-year-old woman crippled by RA and bound to the wheelchair, recovered rapidly and 'within a week she walked out of the hospital in a gay mood and went on a shopping trip for three hours'.[26] The new treatment option for RA was enthusiastically acclaimed and rapidly considered a kind of a miracle drug. In order to prevent confusion with vitamin E, Hench later named it cortisone, as an acronym for corticosterone.[16,27] Only 2 years later, in 1950, Hench and Kendall (together with Reichstein from Switzerland, who had independently isolated cortisone) jointly received the Nobel Prize in Physiology or Medicine—to this day the only Nobel Prize ever granted in the field of rheumatology. Inspired by the work of Hench and Kendall, Selye tried cortisone on his laboratory rats and confirmed that it was indeed the central substance of his stress reaction. Together with its derivatives, he categorized it under the term GCs—introducing a word that has since become part of our basic medical vocabulary.[14,28]

As the effectiveness of GCs was unrivalled at that time, they quickly became the central element in the pharmacological treatment of RA and were widely prescribed in high doses over lengthy periods.[20] However, this extensive use rapidly revealed the unacceptable adverse effects of long-term high-dose treatment, leading to great precautions regarding their prescription. GCs lost their importance as a first-line treatment option in RA and mainly remained a treatment of last resort for particularly severe cases.[1] The scientific interest in the formerly alleged miracle drug vanished. Until 1990, <10 controlled trials regarding the anti-rheumatic efficacy of GCs were conducted with a total of only ~100 patients included in the GC arms.[1] In certain other conditions however, including various forms of vasculitis, inflammatory myopathies and several non-rheumatic diseases like asthma, GCs have remained among the central treatment elements and are therefore considerably better studied regarding their effects.

Since that time we have witnessed the advent of numerous new pharmacological treatment options for RA. However, recent innovations (particularly biologics) are often expensive, cannot achieve sufficient disease control in all patients[29] and may themselves present serious safety concerns.[30] GCs on the other hand are widely and cheaply available and are still among the drugs with the best anti-inflammatory effect. Besides, evidence keeps accumulating that they not only provide symptomatic relief, but also carry a disease-modifying potential if administered as a low-dose co-medication in RA. And not only does the risk of adverse effects induced by low GC dosages seem to be significantly lower than suspected for a long time, the adverse effects themselves are also far better manageable nowadays.[1] Therefore GCs remain—or maybe have once again become—an important element in the pharmacological management of RA and other (rheumatic) diseases.

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