Glucocorticoids have undoubtedly saved the lives of many children, whether to control asthma, inflammatory bowel disease, muscular dystrophy, or autoimmune diseases such as lupus.  However, chronic use of what is essentially a synthetic hormone in a child can lead to a horrific range of side-effects such as stunted growth, delayed puberty, and even impaired neurodevelopment. These problems can persist for the remainder of the child’s life, and in some cases, the drugs that have saved their lives, have taken away their hopes for a “normal” future. 

Fortunately, alternative medications, such as effective immunomodulatory agents and biologic drugs, offer hope and enable pediatricians to reduce the use of steroids in their patients, and minimize (or even eradicate) these long-lasting steroid scars.

In order to ensure that medications can be properly assessed and evaluated for their ability to not only reduce symptoms but also reverse steroid-toxicity a standardized measure is needed. The Steritas Glucocorticoid Toxicity Index (GTI) provides this measure for adults [1] and is already being used in more than 40 studies worldwide. 

However, measuring steroid-toxicity in children is more complex than in adults, as any assessment must consider the impact of both age and sex reference ranges. In order to account for these additional complexities John Stone MD MPH, the developer of the GTI, assembled a group of fourteen pediatric specialists to address the problem. These physicians represented multiple sub-specialties in which glucocorticoids play an important role in the treatment of inflammatory diseases.

The result of this global effort, was the development of the Pediatric Glucocorticoid Toxicity Index (pGTI) - a standardized, weighted clinical outcome assessment that can be used across pediatric disciplines to assess steroid-toxicity over time in an age range of 2-18 years. This exciting advance has been published in Seminars in Arthritis and Rheumatism [2].

“The development of the pGTI is an exciting advancement that will enable pediatricians to measure and monitor the worrisome effects that glucocorticoids have on children, and support the development of new therapies that provide pediatricians new, safer therapies,” said Dr John Stone. 

Why a pediatric GTI is so important

One of the most concerning effects of glucocorticoids on children is their impact on children’s growth and development - even leading to adverse effects in puberty. To fully address these developmental impairments, any measurement instrument needs to consider the impacts of both age and sex, leading to several important differences between the pGTI and the adult GTI:

1. The pGTI includes an entirely new domain: growth.
2. The pGTI algorithm considers pediatric height and sex-specific reference ranges for blood pressure and age-related references for other parameters.
3. The more nuanced neuropsychiatric domain of the pGTI includes aspects of neurological development unique to the pediatric population.

4. There are slight differences in the numerical value of the weights for comparable domains between the pGTI and the adult GTI. This reflects differences in the relative importance of specific steroid-toxicities in the two populations, but overall, the trends in the weights are quite similar.

When children are treated with steroids at age 10, it can affect their quality of life – and morbidity – for decades. To ensure the most effective and safest possible treatment, measuring potential damage is vital.

How were the candidate domains selected and measured?

The pGTI provides an assessment of steroid-toxicities that are common, important, and dynamic. Candidate glucocorticoid-related toxicities were generated based on a literature review and consensus exercises. Each toxicity was assigned to a specific health domain (e.g., body mass index, glucose metabolism, or infections). The domains were then classified as minor, moderate, or major and weighted according to severity. Relative weights were determined by group consensus and multi-criteria decision analysis using the 1000Minds^TM software platform.

The overall toxicity profile derived from the pGTI data consists of two quantitative scores: the cumulative worsening score and the aggregate improvement score. The pGTI also includes a qualitative, unweighted record of adverse effects called the Damage Checklist, which documents less common toxicities that can be serious but are unlikely to change with different steroid doses.

How was the pGTI evaluated?

The performance of the pGTI was evaluated by the participating experts to assess the consistency of use (reliability) and the extent to which the instrument reflects the experts' clinical assessment of relative steroid-toxicity (face validity). 107 toxicity items were included in the pGTI and 32 in the Damage Checklist. To assess the extent to which the pGTI reflected expert clinical judgment, investigators ranked 15 cases from highest to lowest steroid-toxicity by clinical judgment. Expert rankings were then compared to case ranking by the pGTI, yielding excellent agreement.

Conclusion

The newly developed pGTI represents an important improvement in assessing morbidity associated with glucocorticoid use in children and adolescents. The tool is intended for use in prospective, randomized clinical trials in pediatrics and in pediatric practice. It can be used in all clinical disciplines to measure the impact of steroid-toxicity. The instrument is often used to assess the clinical and economic value of steroid-sparing therapies. Given the widespread use of steroids and the accelerating pace of immunological drug discovery, this tool represents a significant advance in our ability to evaluate the utility of new pharmacological agents.

References

[1] John H. Stone, P. Jane McDowell, David R.W. Jayne, Peter A. Merkel, Joanna Robson, Naomi J. Patel, Yuqing Zhang, Huibin Yue, Pirow Bekker, Liam G. Heaney, The glucocorticoid toxicity index: Measuring change in glucocorticoid toxicity over time, Seminars in Arthritis and Rheumatism, Volume 55, 2022, 152010, ISSN 0049-0172, https://doi.org/10.1016/j.semarthrit.2022.152010.

[2] Paul Brogan, Ray Naden, Stacy P. Ardoin, Jennifer C. Cooper, Fabrizio De Benedetti, Jean-Francois Dicaire, Despina Eleftheriou, Brian Feldman, Jon Goldin, Seth E. Karol, Fiona Price-Kuehne, David Skuse, Constantine A. Stratakis, Nicholas Webb, John H. Stone, The Pediatric Glucocorticoid Toxicity Index, Seminars in Arthritis and Rheumatism, 14 July, 2022 152068, https://doi.org/10.1016/j.semarthrit.2022.152068