An estimated 10% of children will receive steroids during their childhood. For many, the treatment is life-saving. For far too many, steroids leave a trail of growth inhibition, delayed puberty, mood disturbance, and metabolic harm that persists throughout their adult lives. Until 2022, there was no standardized, validated tool to measure any of these outcomes in pediatric patients.

That has now changed. The pediatric Glucocorticoid Toxicity Index (pGTI), published in Seminars in Arthritis and Rheumatism in July 2022, was developed by an international panel of fourteen pediatric subspecialists assembled by John Stone, MD MPH, Director of Clinical Rheumatology at Massachusetts General Hospital and the architect of the adult Glucocorticoid Toxicity Index [1]. The pGTI covers patients aged 2 to 17. It is the first weighted clinical outcome assessment built specifically to capture what steroids do to a child's developing body over time.

Children are not small adults

Professor Paul Brogan, MBBS MRCP, Professor of Vasculitis at University College London and Consultant Pediatric Rheumatologist at Great Ormond Street Hospital, helped develop the pGTI and put the problem plainly:

"Kids aren't small adults. You have to score growth, puberty, and neurodevelopment, and weigh a symptom's impact differently in a two-year-old versus a fourteen-year-old."

The adult instrument, used in more than 40 studies worldwide [2], does not account for the parameters that matter most for a growing body. The pGTI includes growth as an entirely new domain. It incorporates pediatric height references and sex-specific blood pressure reference ranges. Its neuropsychiatric domain captures developmental milestones and neurodevelopmental effects unique to children.

Glucocorticoid growth impairment was first documented in 1956 by Blodget and colleagues [3]. Decades later, Mushtaq and Ahmed reviewed the limited data since and called for "improved awareness and better access to measuring and monitoring" of steroid-toxicity and growth impairment [4]. The pGTI answers that call with a validated instrument.

What the data show in children with lupus

The first substantial real-world data from the pGTI in clinical practice came from a study led by Emily Zhang, BS, and Joyce Chang, MD MSCE, at Boston Children's Hospital and Harvard Medical School, in collaboration with researchers at the Children's Hospital of Philadelphia. The retrospective cohort analysis, published in Seminars in Arthritis and Rheumatism in 2024, included 126 pediatric systemic lupus erythematosus (pSLE) patients treated at both centers between 1999 and 2023 [5]. Data were collected at six-month intervals.

The burden was substantial. Nearly half of patients (47%) experienced increased blood pressure, the most frequently observed toxicity. Mood disturbances affected 25%. BMI increases were recorded in 21% of patients. Decreased growth velocity was seen in 18%, a finding that carries consequences extending far beyond the treatment period [5]. The study also found that younger age, elevated BMI at baseline, and the need to add rituximab due to disease severity were significant risk factors for greater cumulative toxicity [5].

A pilot study of 45 pediatric lupus nephritis patients with an average age of 13 years showed that more than half had elevated blood pressure, 11% experienced a hypertensive episode, and 9% had an episode of Posterior Reversible Encephalopathy Syndrome. PRES is a rare but devastating/dangerous condition involving brain swelling that can cause seizures, severe headache, neurologic deficit, and hypertensive emergency. Dr Chang explained the mechanism:

"With regard to PRES, it's not just hypertension causing it. There is also an inflammatory component, and kids with severe disease have a lot of systemic inflammation. So, when we put these things together, it can generate this increased susceptibility."

The mood findings deserve particular attention. In the pilot study, 20% of patients experienced a negative impact on mood. Dr Chang was direct about why those figures may undercount the true burden:

"I don't think we fully appreciate it or capture it, because there are many things that parents don't necessarily tell us in a one-hour visit. Parents have significant concerns about anxiety, depression and hyperactivity, and whether their child will function in school. If we consider how important education is for future health outcomes, parents are right to be concerned."

A separate analysis of 430 children in the UK JSLE cohort study, drawn from 22 pediatric rheumatology centers, found that treat-to-target strategies can deliver measurable reductions in severe flare and organ damage in juvenile lupus. Led by Eve Smith, PhD MBCHB at Liverpool University, the TARGET LUPUS study found that low disease activity and remission targets were achievable in 32% to 73% of patients depending on the measure used [6]. Increasing cumulative time in the Lupus Low Disease Activity State (LLDAS) target from 10% to 80% reduced the hazard of severe flare from 0.68 to 0.05 [6]. The authors of the patient and parent qualitative study called for inclusion of the pGTI as a validated steroid-toxicity measure in future treat-to-target trials for juvenile lupus [7].

The pediatric evidence base is set out further in Steroid-toxicity in Children: Understudied, not Forgotten and Children Experience High Burden from Steroid-toxicity, with the lupus-specific application in The Steritas pGTI for Pediatric Lupus Management and Treat-to-Target in Juvenile Lupus.

The STAR-JIA trial: pGTI moves into clinical practice

Juvenile idiopathic arthritis is the most common rheumatic disease in children. Steroids (oral and intravenous) and methotrexate remain the standard of care, yet the evidence base for comparative effectiveness, safety, and cost-effectiveness of the two steroid routes is sparse.

The STAR-JIA trial (Steroid TreAtment TRial in JIA) is changing that. Funded by the National Institute for Health and Care Research and led by Associate Professor Clare Pain and Professor Athimalaipet Ramanan,. he trial compares intravenous versus oral steroid regimens in children with JIA across 20 UK sites. It is the first randomized controlled trial to use the pGTI as a tool in the clinic, beyond its role as a research endpoint, administered at Alder Hey Children's NHS Foundation Trust with support from Liverpool Clinical Trials Centre.

Dan Hawcutt, MD MRCPCH, Reader in Pediatric Pharmacology at the University of Liverpool and Honorary Consultant in Pediatrics at Alder Hey Children's Hospital, is the clinical pharmacology lead for STAR-JIA. His take on the data gap:

"The harms caused by steroids are not the most reported side effects because there is still a prevalent misunderstanding that steroid-toxicities are just a cost of doing business."

Dr Hawcutt describes two pediatric populations with steroid exposure. The first is a small cohort with conditions such as JIA, cancer, and Duchenne muscular dystrophy who need high-dose steroids for prolonged periods. The second is far larger: children with eczema, dermatitis, and asthma, where the cumulative number of steroid-exposed children runs into hundreds of thousands.

For STAR-JIA, Dr Hawcutt is explicit about what the pGTI data will enable:

"I'm excited to use the Steritas pGTI to find out what the cost of these regimens are and plot not just the efficacy-dose response curves, but also the side-effect-dose curves. We can then go back to the families and start to offer them discrete choice experiments about the benefits and risks of each approach and start to find the best approaches for each patient."

Associate Professor Pain described what pGTI integration into a trial means for clinical practice:

"By integrating advanced clinical outcome assessments like the pGTI into clinical trials, we are not just advancing research but also directly enhancing clinical practice and patient health."

Professor Brogan made a similar observation from his own clinic:

"The pGTI is designed for clinical trials, but the training to use it has changed my everyday clinic. Now I routinely ask about sleep, mood change, and cosmetic effects that used to be brushed under the carpet. If you can measure steroid-toxicity, you can move it."

Full coverage of the STAR-JIA trial is at Alder-Hey Children's NHS Foundation Trust and Liverpool Clinical Trials Centre led clinical trial to compare effectiveness and to assess steroid-toxicity in children with juvenile idiopathic arthritis. The original case for the pGTI is detailed in Steroid-Toxicity in Children - the Desperate Need for a Pediatric Glucocorticoid Toxicity Index.

What standardized measurement now makes possible

The pGTI is part of the broader GTI Family of clinical outcome assessments that are currently licensed for use across more than 35 diseases in 80 countries. For pediatric clinicians, drug developers, and HEOR teams, the instrument changes the terms of the conversation.

Dr Hawcutt set out the path from trial data to practice:

"If we could ensure standardized data collection at scale using the pGTI, it would help rationalize the prescribing advice for steroids across all sub-specialties, develop richer data sets, associate genetic polymorphisms with the risks of side effects, and build personalized treatment plans."

That vision of pharmacogenomic steroid prescribing is not speculative; the analytical infrastructure now exists to make it a reality.

For any pediatric trial evaluating a steroid-sparing agent, the pGTI answers the most commercially and clinically relevant question: does the new therapy reduce steroid-toxicity. With a pediatric-specific measure, researchers have a reliable answer.

References

1. 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

2. 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

3. Blodget FM, Burgin L, Iezzoni D, Gribetz D., Talbot NB., Effects of prolonged cortisone therapy on the statural growth, skeletal maturation and metabolic status of children. N Engl J Med. 1956 Apr 5;254(14):636-41. https://doi.org/10.1056/NEJM195604052541402

4. Mushtaq T, Ahmed SF. The impact of corticosteroids on growth and bone health. Arch Dis Child. 2002 Aug;87(2):93-6. https://doi.org/10.1136/adc.87.2.93

5. Emily Zhang, Sarah Capponi, Rebecca Scobell, Gabrielle Alonzi, Madeline Hlobik, Ankana Daga, Esra Meidan, Holly Wobma, Liyoung Kim, Lauren A. Henderson, Siobhan Case, Peter A. Nigrovic, John H. Stone, Karen H. Costenbader, Mary Beth F. Son, Joyce C. Chang, Real-world application of the pediatric Glucocorticoid Toxicity Index in childhood-onset lupus, Seminars in Arthritis and Rheumatism, Volume 68, 2024, 152516, https://doi.org/10.1016/j.semarthrit.2024.152516

6. Smith EMF, Tharmaratnam, K Al-Abadi E et. al. Attainment of low risk disease activity and remission targets reduces the risk of severe flare and new damage in childhood lupus Rheumatology 61: 3378-3389, 2022. doi.org/10.1093/rheumatology/keab915

7. Smith EMF, Gorst SL, Al-Abadi E, Hawley DP et. al. 'It is good to have a target in mind': qualitative views of patients and parents informing a Treat to Target clinical trial in juvenile-onset systemic lupus erythematosus. Rheumatology, 60:5630-5641, 2021. doi.org/10.1093/rheumatology/keab173