The Glucocorticoid Toxicity Index-Metabolic Domains, an abridged version of the Glucocorticoid Toxicity Index: post-hoc analysis of data from the ADVOCATE trial

Naomi J. Patel, David R.W. Jayne, Peter A. Merkel, Pirow Bekker, Yuqing Zhang, Pamela Jane McDowell, Joslin Johal, Liam Heaney, Dedee Murrell, Martha Stone, Huibin Yue, John H Stone

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Background: Quantifying glucocorticoid (GC) toxicity is critical to efforts to reduce it. The Glucocorticoid Toxicity Index (GTI) measures toxicity effectively in clinical trials by calculating two scores, the Cumulative Worsening Score (CWS) and the Aggregate Improvement Score (AIS). In clinical practice, however, high patient volumes limit time for standardized assessments. An abbreviated version of the GTI, the GTI-MetabolicDomains (GTI-MD), may help address this issue.

Methods:The GTI-MD is comprised of the Body Mass Index, Glucose Tolerance, Blood Pressure, and Lipid Metabolism domains. We used data from ADVOCATE, a phase 3trial in which avacopan replaced a standard prednisone taper in ANCA-associated vasculitis, to test the ability of the GTI-MD to differentiate the two groups by GCtoxicity. Data from two different disease cohorts, one comprised of patients with asthma and the other of patients with autoimmune blistering disease, constituted the validation set.

Findings: ADVOCATE trial subjects with complete data were analyzed (321 at week 13; 307 at week 26). Both groups’ mean age was 61 years. Men constituted 59% (98/166) and54% (88/164) of the avacopan and prednisone groups. The validation set included 159patients (89 with GC-dependent asthma [40/89 (45%) men]; and 70 with autoimmune blistering disease of the skin [30/70 (43%) men]). The Spearman rank correlation coefficient in ADVOCATE for the GTI-MD CWS with the GTI CWS for the treatment Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation groups combined was 0.78 (95% confidence interval (CI): 0.75, 0.81; P < 0.0001). The corresponding correlation for the AIS was 0.73 (95% CI: 0.69, 0.77; P < 0.0001). The GTI-MD distinguished the groups by GC toxicity at both 13 and 26 weeks. The mean GTI-MD CWS was lower in the avacopan group, consistent with less toxicity (15.9versus 23.0 at 13 weeks [P = 0.0010]; 26.7 versus 31.7 at 26 weeks [P = 0.0092]). The GTI-MD AIS values were also consistent with less toxicity in the avacopan group (2.5versus 13.0 at 13 weeks [P = 0.0003], 4.4 versus 10.1 at 26 weeks [P = 0.0274]).A GTI-MD score of zero corresponded to a low likelihood of toxicity in the other GTIdomains. In the validation set, the Spearman rank correlation coefficient for the GTIMD CWS with the GTI CWS was 0.61 (95% CI: 0.50, 0.70; P < 0.0001) and the corresponding correlation for the AIS was 0.58 (95% CI: 0.47, 0.68; P < 0.0001).

Interpretations: The GTI-MD correlates well with the full GTI and may be incorporated readily into routine clinic workflows without additional input from the clinician. Using the GTI-MD in the background of electronic medical records systems may help clinicians monitor GC toxicity longitudinally, with the goals of preventing the burden of chronic, treatment related suffering and reducing long-term costs to health systems.
Original languageEnglish
Pages (from-to)E413-E421
Number of pages9
JournalThe Lancet Rheumatology
Issue number7
Publication statusPublished - Jul 2023


  • Toxicity
  • Steroids
  • Severe asthma
  • Glucocorticoid toxicity index (GTI)


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