Patients receiving oral steroids for three to four years carry twice the risk of death compared with steroid-naive control groups. That figure comes from a 2022 population-based study of 223,211 oral steroid users conducted by researchers at the University of Gothenburg in Västra Götaland, Sweden. The mortality rate among steroid users was 31.98 deaths per 1,000 patient-years, against 14.05 in the control group. The causes were not obscure: pulmonary embolism, sepsis, and pneumonia.^[1] Long-term steroid usage is associated with mortality in ways that are predictable, documented repeatedly, and until recently, left unmeasured at the point of care.

This is the problem at the heart of steroid treatments. Roughly 50 million adults worldwide, 1% of the adult population, are on long-term glucocorticoids. The drugs cost pennies a day, require no insurance authorization, and work fast. The harm they cause over years has, for the most part, been treated as background noise rather than a quantifiable clinical reality. The field is changing. But it is worth defining steroid-toxicity, understanding why measurement was so slow to arrive, and what drives costs when it is ignored.

Dose is a poor proxy for patient harm

Dose reduction alone tells a clinician very little about whether a patient is getting better or worse as a result of treatment. Steroid-toxicity is driven by cumulative exposure absorbed across months or years, not the milligrams prescribed at any single visit.

The Swedish cohort makes this precise. For patients receiving more than 1.5 times the World Health Organization Defined Daily Dose, the risk of death from sepsis is associated with six times that of matched controls; mortality caused by pneumonia was three times higher.^[1] The dose-harm relationship is real and steep. Yet, the field has consistently blurred the distinction between steroid-sparing dose reduction and actual steroid-toxicity sparing. A patient tapered from 40 mg/day to 10 mg/day has a reduced dose. Whether they have reduced organ damage is a separate question, and answering it requires measurement.

John Stone, MD MPH, Professor of Medicine at Harvard Medical School, the Edward A. Fox Chair in Medicine at MGH, and co-developer of the Glucocorticoid Toxicity Index, has argued that quantifying toxicity change over time is the only way to give clinicians and trial sponsors the evidence base they need to act. The GTI was built on exactly that logic: capture and score whether change across multiple organ systems improves or worsens from one assessment to the next. In 1960, more than 80 distinct steroid-toxicities had been cataloged. Measurement tools capable of capturing them simultaneously arrived only in 2016.

The cumulative burden across organ systems

A systematic literature review by Rice and colleagues, published in Clinical Therapeutics in 2017, surveyed the adverse effect profile of long-term systemic steroid exposure. Hypertension appeared in more than 30% of patients. Bone fracture occurred in 21%-30%. Cataracts in 1% to 3%. Hyperglycemia, weight gain, gastrointestinal complications, and type 2 diabetes recurred throughout. Treatment guidelines to prevent these outcomes, such as bisphosphonate prophylaxis, were rarely followed consistently.^[2]

In lupus nephritis, the reckoning is sharper still. Researchers at The Catholic University of Korea, Department of Rheumatology, led by Joo and colleagues, followed patients enrolled in the Hanyang BAE Lupus observational cohort and found that 22.7% of lupus nephritis patients developed steroid-associated organ damage, compared with 9.8% in those without nephritis. Cumulative glucocorticoid exposure in the nephritis group averaged 27.0 grams, against 14.2 grams in the non-nephritis group.^[3] Steroid-toxicity in lupus nephritis was associated with measurably higher damage burden than the disease activity itself. Michelle Petri, MD MPH, lupus expert at Johns Hopkins, has put the figure even more directly, noting that up to 80% of organ damage in systemic lupus erythematosus is attributable to steroids.

In pediatrics, the harm is compounded. Around 10% of children require some form of glucocorticoid during childhood, according to Aulakh and Singh.^[4] In children, that exposure intersects with growth, bone mineralization, pubertal development, and neurodevelopment. Joyce Chang, MD MSCE, a pediatric rheumatologist and Assistant Professor of Pediatrics in the Division of Immunology at Boston Children's Hospital and Harvard Medical School, is direct about the stakes:

"Steroid-toxicity is an even bigger problem for children than it is for adults. On top of the side effects experienced by adults, steroids can permanently impact a young person's growth and pubertal development."

Chang is concerned with the biggest early morbidity and mortality risk: "steroids dramatically increase the risk of infection." These pediatric exposures remain seriously understudied despite the fact that steroid-toxicity in children carries consequences across the whole of adult life.

In inflammatory bowel disease, a retrospective analysis of 283,970 IBD patients by Farraj and colleagues found that those with chronic steroid use or a history of systemic steroid therapy faced 1.9 times the odds of osteoporosis, 2.1 times the odds of opportunistic infection, a tenfold increase in Cushing's syndrome incidence, and a ninefold increase in adrenal insufficiency.^[5] Despite these documented risks, IBD patients remain overexposed to steroids at rates that continue to rise, particularly among patients with moderate to severe disease.

The economic cost to systems and patients

The economic weight of steroid-toxicity is real and dose- and patient-dependent. The annual incremental cost of managing steroid-toxicity ranges from $5,700 for low-dose users (below 7.5 mg/day) to $29,000 for high-dose users (above 15 mg/day), according to the Rice et al. systematic review.^[2] In rheumatoid arthritis, Pisu and colleagues estimated that for every dollar spent on glucocorticoids, an additional $0.46 was required to treat the resulting adverse events.^[6] That is a 46% surcharge on every steroid prescription, billed not at the pharmacy counter but in emergency admissions, specialist consultations, and long-term disease management.

In asthma, where steroids affect approximately 6% of the global population, more than 300 million people, the cost structure is similarly striking. A healthcare cost analysis by Barry and colleagues found that average annual healthcare costs per person ranged from £2,603 to £4,533 for patients with severe asthma, against £560 to £1,324 for non-asthma controls. Osteoporosis-related costs ran 4.3 times higher in the severe asthma cohort. Osteopenia-related costs ran four times higher.^[7] The healthcare cost of steroid-toxicity across indications is neither hidden nor small.

Despite this, more than 60% of patients on long-term glucocorticoids are not monitored for steroid-toxicity, according to Fardet and colleagues.^[8] James T. Rosenbaum, MD, a rheumatologist and ophthalmologist, has described steroids as operating somewhat like a dependency: effective, immediate, and easy to prescribe, but producing cumulative suffering over time. "Steroid-toxicity is rampant, and it can be fatal," he stated.

"Bringing it onto the radar screen of the practicing physician is really, really important."

Michelle Petri has argued that the prescribing culture itself has to shift:

"There has to be an acceptance that steroids are now an undesirable part of treating most rheumatic diseases, and our prescribing behavior must change."

On the payer side, she adds:

"Reducing steroids improves care and reduces costs. This would help insurance companies come on board because steroid use leading to chronic damage leads to a huge increase in care costs."

Measurement changes the conversation

The GTI has now been deployed as a pre-specified endpoint in phase 3 trials across several diseases. Three 2026 readouts make the point. REPLENISH, in polymyalgia rheumatica, doubled sustained remission with secukinumab versus placebo and recorded a clinically meaningful reduction in steroid-toxicity across every GTI domain.^[9] INDIGO, in IgG4-related disease, cut disease flares by 56% with obexelimab and showed GTI reductions across the majority of domains.^[10] GCAptAIN, in giant cell arteritis, missed its primary remission endpoint, yet the GTI still showed significantly lower steroid-toxicity in the higher-dose secukinumab arm, a benefit a dose metric alone would have missed.^[11] The GTI has now been licensed in more than 35 diseases across 80 countries.

For drug developers, the implication is direct: a steroid-toxicity endpoint is no longer experimental. Trials that quantify what measuring steroid-toxicity means in practice are building a label claim from the protocol stage. For HEOR researchers, the cost data are now sufficient to model lifetime steroid burden against treatment alternatives in a way that payers can interrogate. The GTI-MD, the point-of-care instrument in the GTI Family, also opens possibilities for population health analytics: steroid-toxicity burden can be unmasked in large claims datasets. The first toxic dose of steroids was administered on September 4, 1948, and within twenty-three days the first toxicity appeared. And on the following day, the first taper began. The first validated instrument to measure steroid-toxicity was developed 70 years later.

Clinicians now have a tool to track harm before it becomes irreversible. Drug developers have an essential end point for efficacy. HEOR researchers have a measure that converts toxicity reduction into cost-avoidance.

Payers have the argument Michelle Petri laid out plainly: the steroid-toxicity problem is not hidden, and its costs are not abstract. The 50 million patients on long-term glucocorticoids are, right now, accumulating damage that can be detected, quantified and treated. The case for measurement is not theoretical. It is economic, clinical, and overdue.

References

1. Einarsdottir MJ, Ekman P, Molin M, Trimpou P, Olsson DS, Johannsson G, Ragnarsson O. High Mortality Rate in Oral Glucocorticoid Users: A Population-Based Matched Cohort Study. Front Endocrinol (Lausanne). 2022 Jul 8;13:918356. doi: 10.3389/fendo.2022.918356. PMID: 35872995; PMCID: PMC9304700.

2. Rice JB, White AG, Scarpati LM, Wan G, Nelson WW. Long-term Systemic Corticosteroid Exposure: A Systematic Literature Review. Clin Ther. 2017 Nov;39(11):2216-2229. doi: 10.1016/j.clinthera.2017.09.011. Epub 2017 Oct 19. PMID: 29055500.

3. Joo YB, Won S, Choi C-B and Bae S-C.  Lupus nephritis is associated with more corticosteroid-associated organ damage but less corticosteroid non-associated organ damage.  Lupus 26:598-605, 2017. DOI: 10.1177/0961203316671813

4. Aulakh, R., Singh, S. Strategies for minimizing corticosteroid toxicity: A review. Indian J Pediatr 75, 1067–1073 (2008). https://doi.org/10.1007/s12098-008-0211-6

5. Farraj KL, Pellegrini JR, Munshi RF, Russe-Russe J, Kaliounji A, Tiwana MS, Srivastava P and Subramani K. Chronic steroid use: An overlooked impact on patients with inflammatory bowel disease. J Gastro. & Hepatol. 6:910-914. (2022). https://doi.org/10.1002/jgh3.12841

6. Pisu M, James N, Sampsel S, Saag KG. The cost of glucocorticoid-associated adverse events in rheumatoid arthritis. Rheumatology (Oxford). 2005 Jun;44(6):781-8. doi: 10.1093/rheumatology/keh594. Epub 2005 Mar 15. PMID: 15769791.

7. Barry LE, Sweeney J, O'Neill C, Price D, Heaney LG. The cost of systemic corticosteroid-induced morbidity in severe asthma: a health economic analysis. Respir Res. 2017 Jun 26;18(1):129. doi: 10.1186/s12931-017-0614-x. PMID: 28651591; PMCID: PMC5485660.

8. Laurence Fardet, MD, PhD, Irene Petersen, PhD, and Irwin Nazareth, MD, PhD Monitoring of Patients on Long-Term Glucocorticoid Therapy- A Population-Based Cohort Study. Medicine. Volume 94, Number 15, April 2015

9. Stone JH, Buttgereit F, Saraux A, et al. Phase 3 Trial of Secukinumab in Polymyalgia Rheumatica. New England Journal of Medicine. 2026; Published online June 3, 2026. https://doi.org/10.1056/NEJMoa2602567

10. Della-Torre E, Baker MC, Zhang W, et al; INDIGO Trial Investigators. Obexelimab for the Treatment of IgG4-Related Disease. N Engl J Med. 2026. https://doi.org/10.1056/NEJMoa2601337

11. Stone JH, Venhoff N, Buttgereit F, et al. Secukinumab for Giant Cell Arteritis. NEJM Evidence. Published online June 3, 2026. https://doi.org/10.1056/EVIDoa2600112