A new study published in Lancet Rheumatology [1] by an international team of clinical researchers has highlighted how pervasive and nuanced steroid-toxicity is and how important it is to have a composite measure to capture and quantify the impact of glucocorticoids.

The researchers, led by John Stone MD. MPH, Edward Fox Chair of Medicine and Professor of Medicine at Harvard Medical School and principal developer of the Steritas Glucocorticoid Toxicity Index (GTI), evaluated data collected during the ADVOCATE clinical trial to compare in detail the treatment group differences in steroid-toxicity expression.

The ADVOCATE clinical trial was conducted to evaluate whether avacopan could replace a glucocorticoid tapering regimen used in the treatment of ANCA-associated vasculitis [2]. Glucocorticoid induced toxic effects, as measured by the GTI, were a secondary endpoint of the trial, which demonstrated superiority of avacopan to a prednisone-based standard of care with respect to sustained remission at 52 weeks. 

During the trial, the avacopan group also achieved lower overall GTI values than the prednisone group, indicating reduced steroid-toxicity. Following these results, the FDA approved avacopan as an adjunct therapy to remission induction regimens for ANCA-associated vasculitis.

This latest study looked to understand what insights could be gained from how patients in the trial responded in each of the eight individual domains of the GTI: Body Mass Index, Glucose Tolerance, Lipid Metabolism, Blood Pressure, GC Myopathy, Skin, Neuropsychiatric, and Infection.

The benefits made possible by avacopan to discontinue glucocorticoids early were experienced across multiple domains of toxicity. It is worth observing, however, that despite the strong impact made by avacopan on steroid-toxicity compared to the prednisone regimen, overall 91% of patients in the trial experienced some steroid-toxicity. Moreover, individual patients typically had toxicity documented in multiple domains.

Indeed, 67% of patients had evidence of toxicity in more than one (and up to six) domains, highlighting the challenges posed to clinicians at the point of care to identify, track, and prevent steroid-toxicity. 

The researchers also found that individual patients frequently had improvement and declines in different domains - emphasizing the value of a composite measure such as the GTI that captures the nuances of steroid-toxicity and is able to measure improvement as well as deterioration as a result of these treatments.  

Scores from three domains differentiate the groups with regard to glucocorticoid toxicity as early as 13 weeks in a statistically significant manner. These domains were Body Mass Index, Lipid Metabolism, and Skin Toxicity. Overall, the directionality of 7 of the 8 GTI domains favored the avacopan group (the 8th domain, Blood Pressure, suggested equal glucocorticoid toxicity in both groups)

In summary, the ADVOCATE trial results confirm that a decrease in steroid-toxicity can be regarded not only as an improvement in safety with a new treatment regimen, but also as a marker of treatment efficacy. It also underscores the importance of continued efforts to reduce the frequency with which patients experience steroid-toxicity, even with the advance in treatment provided by avacopan.

References

[1] Naomi J Patel, David R W Jayne, Peter A Merkel, Pirow Bekker, Yuqing Zhang, Huibin Yue, John H Stone, Glucocorticoid Toxicity Index scores by domain in patients with antineutrophil cytoplasmic antibody-associated vasculitis treated with avacopan versus standard prednisone taper: post-hoc analysis of data from the ADVOCATE trial, The Lancet Rheumatology, Volume 5, Issue 3, 2023, 130-138, DOI: 10.1016/S2665-9913(23)00030-9

[2] Jayne DRW, Merkel PA, Schall TJ et al. Avacopan for the Treatment of ANCA-associated Vasculitis. N Engl J Med 2021; 384(7):599-609. DOI: 10.1056/NEJMoa2023386