On September 4, 1948, a bed-ridden 24-year-old woman with rheumatoid arthritis received the first dose of a glucocorticoid. The next morning she could walk. Twenty-three days later, her physicians documented the first steroid-toxicity. The next day, the first taper began. That compressed sequence of miracle, harm, and attempted correction has been playing out across medicine ever since, and 78 years on the field is still working through its implications.

Rheumatoid arthritis (RA) affects 1% of the global population, with twice as many women impacted as men. Steroids arrived into that burden as a revelation. The word "astonished" appears in contemporaneous accounts of the 1948 case, and the astonishment was justified: cortisone delivered rapid, effective reduction of inflammation in a disease that had no equivalent option. What followed was adoption at scale, across specialty after specialty, disease after disease, before the full cost of that adoption was understood.

The toxicity inventory was complete within 12 years

By 1960, the full range of more than 80 steroid-toxicities had been described in the literature. Within 12 years of the 1948 first dose, clinicians had catalogued high blood pressure, osteoporosis, muscle weakness, acne, diabetes, cushingoid appearance, psychosis, and infection vulnerability, among others. The debate about proper steroid use was already underway. The drugs had already become, in the words commonly applied to them, "necessary evils."

What did not exist was a validated way to measure and aggregate those harms over time in individual patients. That gap persisted for more than half a century. The challenges of quantifying such a wide range of toxicities in a single instrument were not addressed until 2016, when a group of subspecialty experts from around the world convened to develop the Glucocorticoid Toxicity Index (GTI), the validated clinical outcome assessment now at the center of steroid-sparing research.^[1] The GTI Family of instruments now includes the GTI, the pediatric pGTI, and the GTI-MD for point-of-care clinical monitoring.

A Nobel Prize created an infrastructure problem

Drs Philip S. Hench, Edward C. Kendall, and Tadeus Reichstein identified the hormones that became steroids and were awarded the 1950 Nobel Prize in Medicine. The prize cemented institutional prestige around these compounds at the precise moment clinicians were beginning to document their harms. That combination, a Nobel-validated drug class arriving into medicine before regulatory frameworks matured, created the infrastructure problem that Ali A. Habib, MD and Pushpa Narayanaswami, MD later put directly in an editorial published in the journal Muscle and Nerve: would glucocorticoids be approved if discovered today?^[2]

Their answer, examined through modern regulatory standards, is that the question is genuinely debatable. The extensive adverse events associated with steroids make their risk-benefit ratio, viewed from scratch, a difficult case. If a more recently introduced medication caused the same range and severity of harms, the authors ask, would it remain on the market? The question is a genuine clinical and policy challenge, and it has received too little formal attention given the scale of the population exposed.

More than 50 million adults are on chronic glucocorticoid treatment worldwide. Habib and Narayanaswami cite a survey of Canadian neuromuscular neurologists examining their management of chronic steroid therapy, which found substantial variability in screening, monitoring and prophylaxis.^[3] Most clinicians discussed osteoporosis and hyperglycemia with patients. Vaccination recommendations and other preventive measures were applied inconsistently. The regulatory question and the clinical-practice question turn out to be the same question: these drugs were never properly operationalized into a monitoring standard.

Steroids have a role in treating so many diseases, and yet cure none of them

John H. Stone, MD MPH, Professor of Medicine at Harvard Medical School, and the Edward A. Fox Chair in Medicine at the Massachusetts General Hospital, put the central paradox plainly in conversation with Steritas:

"Steroids have a role in treating so many diseases, and yet, they do not cure any of them."

That sentence contains the entire problem. The short-term anti-inflammatory effect is real and often necessary. The disease, in most cases, persists. The patient stays on the drug. The toxicity accumulates. In the second edition of A Clinician's Pearls and Myths in Rheumatology, which Dr Stone edited with contributions from more than 200 clinical experts and which saw more than 7,000 downloads in its first two weeks, he identified steroid overuse as a thread running through chapter after chapter across specialties. His framing in that book is precise:

"I often think that steroid-toxicity is a bit like the wallpaper in the examining room. It's there while the physician and patient are having their encounter, but too often it is completely ignored, not addressed, and allowed to grow worse."

That wallpaper metaphor captures something particular about how the field arrived at its current position. Steroid-toxicity has been visible since 1948. What the field lacked was a systematic response to knowledge that clinicians had possessed for decades.

What the taper data reveals

The timing of dose reduction matters more than physicians once assumed, and recent longitudinal data puts specific numbers to the consequences of getting it wrong.

A three-year observational study of 89 patients with severe asthma, published in the Journal of Allergy and Clinical Immunology: In Practice, tracked steroid-toxicity using the GTI at baseline, year 1, and year 3 following biologic treatment.^[4] The study, led by P. Jane McDowell, MBBS BSc PhD, academic clinical lecturer at Queen's University Belfast, built on the group's first GTI quantification in severe asthma^[5] and an earlier one-year study of 101 patients treated with mepolizumab.^[6] It found that roughly 30% of patients showed no significant improvement in toxicity at either year 1 or year 3, even as their oral steroid exposure was substantially reduced.

Dr McDowell stated:

"It is disheartening to report that a considerable number of patients do not have much toxicity improvement even when steroid exposure is negligible."

The study showed that GTI scores at year 1 predict outcomes at year 3, creating an early identification window: patients not showing toxicity reduction after the first year of biologic treatment can be identified and managed before longer-term morbidity accumulates.

For patients who do show improvement, the economic signal is also present. A median 0.9-point improvement in the EuroQol Utility index across the full cohort translates to a gain of one quality-adjusted life year if sustained over 11 years, with an estimated economic value of approximately £20,000 to £30,000 per patient. Steroid-sparing is a clinical imperative. It is also a health economics argument with specific numbers behind it.

The modern standard of care requires measurement

The GTI Family of instruments has now been licensed in more than 35 diseases across 80 countries. The instruments are now informing trial design, health economics modeling, and point-of-care monitoring. Martha Stone, CEO of Steritas, has noted that tapering in clinical trial protocols, where patients may move from 60 mg per day to zero in 12 weeks, does not reflect clinical practice, where the path to a 5 mg maintenance dose may take a year or more, often because physicians lack a method to measure steroid-induced harm as it accumulates in real time.

Frank Buttgereit, MD, a long-term collaborator in the field, stated the operating principle concisely:

"Every milligram that helps control the disease is a good milligram, but every milligram we can spare is an even better one."

The 1948 patient who rose from her bed the morning after her first dose changed the trajectory of inflammatory disease management. The taper that began 23 days later was the first acknowledgment that the gain came with a cost. Seventy-eight years on, the field has the instruments to measure that cost with precision. The question facing rheumatologists, drug developers, health economists, and payers now is whether the clinical and commercial infrastructure will organize around measurement before another generation of patients accumulates toxicity that, in a meaningful proportion of cases, turns out to be irreversible.

References

1. Miloslavsky EM, Naden RP, Bijlsma JWJ et al. Development of the Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis. Ann. Rheum. Dis. (2017). 76:543-546. https://doi.org/10.1136/annrheumdis-2016-210002

2. Habib AA, Narayanaswami P. Would glucocorticoids be approved for clinical use if discovered today? Muscle Nerve. 2024 Jul;70(1):9-11. Epub 2024 May 8. PMID: 38720486. https://doi.org/10.1002/mus.28111

3. Stepanian L, Laughlin R, Bacher C, et al. Chronic glucocorticoid management in neuromuscular disease: a survey of neuromuscular neurologists. Muscle Nerve. 2024;70(1):52-59. https://doi.org/10.1002/mus.28069

4. McDowell PJ, Busby J, Stone JH, Butler CA, Heaney LG. Longitudinal assessment of glucocorticoid toxicity reduction in patients with severe asthma treated with biologic therapies. J Allergy Clin Immunol Pract. 2025;13(2):298-307.e10. https://doi.org/10.1016/j.jaip.2024.10.024

5. McDowell PJ, Stone JH, Zhang Y, Honeyford K, Dunn L, Logan J et al. Quantification of glucocorticoid-associated morbidity in severe asthma using the Glucocorticoid Toxicity Index. The Journal of Allergy and Clinical Immunology: In Practice. 9: 365-372. 2021. https://doi.org/10.1016/j.jaip.2020.08.032

6. McDowell PJ, Stone JH, Zhang Y, Honeyford K, Dunn L, Logan RJ, McGarvey LPA, Butler CA, Heaney LG. Glucocorticoid toxicity reduction with mepolizumab using the Glucocorticoid Toxicity Index. Eur Respir J. 2022;59(1):2100160. https://doi.org/10.1183/13993003.00160-2021