The true cost of steroid-toxicity 

Glucocorticoids, commonly referred to as steroids, are currently the standard of care for the treatment and management of many autoimmune disorders. They are highly effective at suppressing inflammation and the reducing the activity of the body’s immune system, providing rapid relief from associated symptoms. At the time of prescribing, steroids appear to be a low-cost, accessible solution.

Unfortunately, the clear therapeutic benefits of steroids are overshadowed by the severe side effects that accompany their long-term use, with patients experiencing steroid-toxicity related symptoms including depression, muscle weakening, osteoporosis, and hypertension¹. It has long been known that patients should receive the lowest possible therapeutic dose to minimize toxicities, but progress in the field has been slow, largely due to the lack of practical measurement tools and effective alternatives.

Quantification and monitoring of steroid-toxicity

Through the evaluation of nine health domains, it is possible to standardize the quantification of steroid-toxicity, providing a validated tool for measuring the impact of long-term and high-dose steroid usage on patient quality of life and healthcare resources. Introduction of such clinical outcome assessments (COAs) will improve both drug development and clinical practice, as well as helping to reduce the over-reliance on steroids.

The Glucocorticoid Toxicity Index (GTI)², developed by a group of international clinicians, doctors, and researchers in 2017, simplifies the scoring of steroid-toxicities by generating a Cumulative Worsening Score (CWS) and Aggregate Improvement Score (AIS). Higher scores in both directly correspond to increased steroid-toxicity, enabling early detection of toxicity before it becomes irreversible and evidencing the effectiveness of novel steroid-sparing therapeutics and steroid-tapering approaches.

The GTI forms the basis of a set of tools that demonstrate effectiveness across a variety of therapeutic areas including asthma, arthritis, and juvenile lupus, facilitating a reduction in steroid-prescribing patterns and, where possible, a shift to novel steroid-toxicity sparing therapeutics. The impact of integrating these tools across drug development and into healthcare systems is being increasingly realized, across a growing range of autoimmune disorders.

A novel adjunctive treatment for ANCA – associated vasculitis

ANCA-associated vasculitis is a collection of three vasculitis conditions associated with ANCA, a key protein factor in the blood, which cause inflammation-related damage of small blood vessels in the kidneys, lungs, joints, ears, noses, and nerves. In 2021, the FDA approved avacopan, an orally administered C5 receptor inhibitor, as an adjunctive treatment for adults with ANCA-associated vasculitis following the ADVOCATE trial³, which evaluated whether avacopan could replace a steroid-tapering regime.

As part of the trial, steroid-induced toxic effects were a secondary endpoint, using the GTI to generate CWS and AIS. The avacopan treatment reduced scores across almost all health domains in comparison to treatment with the steroid, prednisone, confirming a statistically significant reduction in steroid-toxicity. Additionally, avacopan demonstrated its superiority in terms of sustained remission at 52 weeks, further evidencing its advantages over prednisone-based treatment plans.

Clinical monitoring using electronic health records

In one example from 2024⁴, the GTI was adapted and simplified for use in clinical settings with a reduced number of metabolic domains that can be captured directly from electronic health records; BMI, blood pressure, glucose tolerance, and lipid metabolism. Through a retrospective, real-world study, researchers evaluated steroid-toxicity in patients with myasthenia gravis, an autoimmune disease in which the immune system attacks neuromuscular junctions to cause muscle weakness, primarily in the face.

The study demonstrated that patients treated with steroids exhibited a significant increase in CWS compared to steroid-naïve patients, as well as indicating an increase in steroid-toxicity in patients that received higher doses or multiple courses of steroids. These findings reflect the potential of steroid-toxicity quantification to be used in health economics outcome research (HEOR) studies, supporting decision making in both drug development and healthcare. 

There is additional ongoing research exploring the ability of the GTI to track steroid-toxicity in myasthenia gravis (MG) patients, and evaluate how well steroid-toxicity scores correlate with established disease outcomes, including the MG-activities of daily living, evaluating how basic self-care functions are affected, MG composite, an outcome measure of signs and symptoms, and MG-QOL15R, a 15-item questionnaire measuring quality of life. Preliminary results show that patients often lack awareness of symptoms associated with steroid-toxicity. 

Routine integration into clinical settings

A prospective clinical study based at a rheumatology outpatient clinic in Turkey⁵ investigated the use of the GTI in patients with inflammatory arthritis (IA), connective tissue disease and vasculitis. Across the steroid-treated patients, a higher cumulative dose was associated with significantly higher CWS and AIS, with increased prevalence of toxicities such as high blood pressure and impaired glucose tolerance. Additionally, GTI scores were higher in patients with vasculitis than patients with IA due to the higher dose required for treatment.

The most interesting finding from this study was that the GTI scores in vasculitis patients remained higher than in IA once the cumulative dose was kept constant in the regression analysis. It was hypothesized that patients with vasculitis have a higher inflammatory response and are therefore more susceptible to steroid-toxicity. 

In this case, the GTI detected prominent differences between patient groups, and can therefore be integrated into daily clinical practice for the detection, monitoring, and management of steroid toxicities. 

The future of treatment for autoimmune diseases

The integration of steroid-toxicity quantification tools into clinical trial workflows will offer a novel approach to evidence-based healthcare research, informing patients and doctors on the detrimental impact of steroid-toxicity and the urgent need for novel steroid-sparing therapeutics. Adaptation of these tools will further expand their utility, enabling application in pediatric patients and other therapeutic areas. This combined approach of quantifying steroid-toxicity in both drug development and steroid tapering will relieve the costly burden of extended steroid use, improving quality of life for all patients living with autoimmune conditions. 

John H Stone, MD MPH graduated from Harvard Medical School and completed his internal medicine training at Johns Hopkins Hospital. He trained in rheumatology at the University of California-San Francisco. Dr. Stone is currently a Rheumatologist and Professor of Medicine at Harvard Medical School, and the Edward A. Fox Chair in Medicine at Massachusetts General Hospital. Dr. Stone led the international group of investigators who developed the Glucocorticoid Toxicity Index (GTI) and serves as Chair of the Scientific Advisory Board at Steritas. 

References 

1. Schacke, H, Docke, W, Asadullah, K (2002). Mechanisms involved in the side effects of glucocorticoids. Pharmacology and Therapeutics, 96: 23–43. Doi:  10.1016/s0163-7258(02)00297-8
2. Stone JH, McDowell, PJ, Jayne DRW et. al., (2022). The glucocorticoid toxicity index: Measuring change in glucocorticoid toxicity over time. Seminars in Arthritis and Rheumatology. 55: 152010. Doi: 10.1016/j.semarthrit.2022.152010
3. Jayne, DRW, Merkel, PA, Schall, TJ et al., (2021). Avacopan for the Treatment of ANCA-Associated Vasculitis. The New England Journal of Medicine. 384 (7): 599-609. Doi: 10.1056/NEJMoa2023386
4. Phillips G, Stone JH, Qi CZ, et al., (2024). Adaptation of the Glucocorticoid Toxicity Index-Metabolic Domains to Electronic Health Records to Evaluate Steroid Toxicity in Adults with Myasthenia Gravis in the United States. Value in Health. 27 (6): S399. Doi: 10.1016/j.jval.2024.03.1864
5. Bahap-Kara, M, Sariyildiz, E, Zengin, HY, et al., (2024). Prospective Assessment of Glucocorticoid Toxicity in Rheumatology Practice: A Focus on the Glucocorticoid Toxicity Index. Rheumatology (Oxford). Keae288. Doi: 10.1093/rheumatology/keae288

 

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