Approximately 13 million people worldwide have severe, uncontrolled asthma even with optimized treatment, according to the Global Initiative for Asthma (GINA). In this population, systemic steroid exposure remains common in real-world care. Yet as Jane McDowell, MBBS BSc PhD and colleagues demonstrated in landmark research, the field still lacks a standard way to quantify the cumulative harm that oral steroid exposure causes at the individual patient level, the gap that defines the steroid-toxicity measurement challenge.

The structural problem with dose-based endpoints

Dose and exacerbation outcome measures are necessary, but not sufficient, when the objective aims to reduce steroid-toxicity and other treatment-related morbidities.

"The real-life burden of steroids is significant, and there is substantial evidence across various disease states showing just how commonly these adverse events occur and at relatively low doses," notes Dr McDowell, Consultant at Queen's University Belfast in Northern Ireland.

At the population level, steroid-related adverse effects often increase with exposure. But at the patient level, toxicity burden varies widely, and steroid exposure history alone does not reliably predict harm. McDowell's research, published in the Journal of Allergy and Clinical Immunology: In Practice, underscores this gap: morbidity is typically summarized in aggregate, while clinicians and sponsors need patient-level measurement to assess trade-offs.

PROMs capture quality of life and disease control, but they don't isolate steroid-toxicity as a distinct, measurable outcome. When development programs rely on dose reduction and exacerbations as proxies, they can only prove "lower dose" rather than "less harm." The most important secondary endpoint for efficacy, steroid-toxicity reduction, remains unmeasured.

What McDowell's research revealed

Dr McDowell and her team conducted an observational cohort study quantifying steroid-associated morbidity in severe asthma using the Glucocorticoid Toxicity Index (GTI). The study assessed 101 patients under routine clinical care, 82% of whom were receiving daily maintenance prednisolone. Disease control and quality-of-life measures were collected alongside systematic toxicity assessment.

The findings were striking. Individual susceptibilities to steroid-toxicity varied widely, even among patients with similar exposure profiles. Baseline steroid exposure proved an unreliable variable for determining which patients should start or continue biologic agents. The investigators concluded that steroid-toxicity may be the best criterion for determining which patients would benefit from biologics in asthma.

"Steroid use is prevalent among severe asthma patients, in part due to physician training that emphasizes the effectiveness of steroids rather than their potential dangers," Dr McDowell observes.

The persistence problem

Dr McDowell's subsequent longitudinal research published in 2024 examined steroid-toxicity reduction in patients with severe asthma treated with biologic therapies over time. The findings challenge a common assumption about reversibility: that reducing exposure will automatically lead to toxicity burden improvement.

The longitudinal data demonstrate why patient-level measurement matters. Lower toxicity is NOT guaranteed by lower exposure. Measuring steroid-toxicity directly is the way to distinguish "lower exposure" from "lower cumulative damage." This insight is critical for pharmaceutical development, where the timing of intervention and the durability of benefit are essential elements of the value proposition.

Direct measurement changes the development equation

The Glucocorticoid Toxicity Index (GTI) provides a direct, validated, structured approach to quantifying steroid-toxicity at the individual patient level. McDowell's work demonstrates that the GTI captures and assesses toxicity systematically. This enables consideration of disease outcomes in the context of steroid-toxicity rather than treating treatment burden as a background safety issue.

Dose is still relevant. But dose alone is an incomplete decision metric when steroid stewardship is part of the value proposition. Dr McDowell's research proves this empirically: what matters is not just how much steroid a patient receives, but how much measurable harm accumulates as a consequence.

What this changes for clinical development leaders:

• Trial design: Add steroid-toxicity reduction as a measurable endpoint alongside dose and exacerbations to demonstrate benefit on the harm steroid stewardship is trying to prevent. McDowell's methodology provides the validated framework.

• Benefit-risk: Balance disease outcomes with steroid burden using direct toxicity measurement. The cohort in the observational research shows that GTI components are distinct, measurable domains.

• Differentiation: Compete on measured steroid-toxicity reduction, not only steroid-sparing alone. McDowell's findings give pharmaceutical sponsors the evidence base to support this positioning.

Why this matters for steroid stewardship

Steroid stewardship remains unresolved in asthma because measurement has only recently made it possible. Dose-based stewardship can hit reduction targets while the patient is still suffering harm. Exacerbation-only assessment conflates disease activity with treatment toxicity. Quality-of-life instruments cannot isolate steroid-toxicity.

Direct toxicity measurement is the missing link: a way to quantify when steroid-sparing strategies deliver steroid-toxicity sparing results. Dr McDowell's research at Queen's University Belfast established the clinical evidence base. Pharmaceutical development now has the tools to act on it.

References

1. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. 2024.

2. McDowell PJ, et al. Quantification of Glucocorticoid-Associated Morbidity in Severe Asthma Using the Glucocorticoid Toxicity Index. Journal of Allergy and Clinical Immunology: In Practice. 2021.

3. 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. Journal of Allergy and Clinical Immunology: In Practice. 2024.