Steroid sparing treatments have long been heralded as an advancement in reducing reliance on steroids; however, reducing steroid dosage does not automatically equate to a reduction in steroid-toxicity.
As John Stone, MD MPH, Professor of Medicine at Harvard Medical School and the Edward A. Fox Chair in Medicine at the Massachusetts General Hospital asserts, there needs to be a systemic shift in how we measure the success of new therapies, especially those for autoimmune inflammatory diseases where steroids are still often overused.
The gap between steroid dosage and toxicity
Dr Stone emphasizes that while steroid sparing drugs may reduce the overall steroid dose a patient takes, this does not necessarily mean they reduce the harmful side effects of steroids.
“Every patient reacts differently to steroids. Measuring the dose is not enough. Directly measuring the toxicity in every patient is the only way to know they have improved from a reduction in steroids.”
Dr Stone recalls a key moment from a study on polymyalgia rheumatica in which the difference in cumulative steroid dose between the treatment and control groups was statistically significant but of dubious clinical significance.
“A new drug was touted for its ability to “spare” steroids, but in fact, the reduction in daily prednisone dose was an amount that many clinicians would view as trivial. There had been no effort to measure the new drug’s ability to reduce not just steroids but steroid-toxicity. In this era, we need to ask pointedly: ‘Does this decrease in prednisone use - which may be partly an artifact of the trial design - deliver a meaningful reduction in steroid-toxicity that we can measure?’”.
Dr Stone cites the ADVOCATE trial for ANCA-associated vasculitis, where patients in the avacopan treatment arm had achieved significantly lower steroid use. However, only by using the Steritas Glucocorticoid Toxicity Index (GTI) could researchers demonstrate that this reduced dose actually led to lower toxicity. According to Dr Stone, this is a critical, often overlooked, step.
The GTI allowed the researchers involved in the ADVOCATE trial to systematically measure steroid-toxicity, showing that their new drug was efficacious and reduced steroid-toxicity that was clinically meaningful to patients.
Why toxicity matters in drug development
Steroid-toxicity causes an array of debilitating side effects, including bone loss, increased infection risk and diabetes. Dr Stone argues that pharmaceutical companies can help justify the use of expensive treatments when they can demonstrate not just a reduction in steroid dosage, but a tangible improvement in steroid-toxicity.
“If a patient is to be prescribed a drug that costs over $50,000 per year, there should be a demonstrable benefit - not just fewer milligrams of steroids used, but less toxicity and better quality of life. The correlation between steroid dose and toxicity is rough and imperfect. Without measuring toxicity directly, we can’t assess the true benefit.”
This disconnect between dosage and toxicity has posed a significant challenge for regulators, pharmaceutical companies and clinicians. The introduction of the GTI and the other clinical outcome assessments in the STOX® Suite have changed the conversation.
“As with any innovation, it was initially difficult to convince clinicians and researchers that measuring steroid-toxicity in all of its complexity was even feasible, never mind essential. It has been enormously gratifying to see the use of the GTI and the full STOX Suite grow rapidly, to the point that these instruments are now used in 30 different disease indications across the inflammatory disease space.
When we are speaking with clinical researchers now, I’m surprised by how many of them know all about the GTI already and recognize the importance of showing reductions in toxicity in clinical trials. The key has been to show just how easy it is to collect these data.”
Dr Stone emphasizes that the clinical outcome assessments in the STOX Suite can not only track toxicity but when combined with large datasets from healthcare systems, but also enable researchers to correlate that data with healthcare costs and outcomes. This ability to anticipate the impact of reduced steroid use on large populations is critical for convincing regulators and payers alike.
What the future holds
Looking forward, Stone believes that all stakeholders - from patients to regulators - need to recognize the importance of measuring and reducing steroid-toxicity. He stressed that clinicians in particular need to integrate this awareness into their practice.
“Clinicians must believe in the data and implement it. Too often, they lean on steroids out of habit, even when alternative treatments could reduce toxicity. It’s a matter of shifting the mindset.”
Dr Stone’s call for a “steroid-toxicity sparing” approach highlights a broader issue: the need for a systemic shift in how we measure the success of new therapies. Reducing steroid dosage is not enough. Only by focusing on toxicity can we truly improve patient outcomes and justify the cost of newer, more expensive treatments.