Avacopan Trial Yields Insight Into Glucocorticoid Toxicity in AAV

Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis treated with avacopan in place of the standard prednisone taper showed lower glucocorticoid toxicity among multiple domains measured by the Glucocorticoid Toxicity Index (GTI), investigators noted in a post-hoc analysis of data from the ADVOCATE trial.

Avacopan, a complement 5a receptor (C5aR) antagonist that blocks C5a-mediated neutrophil activation and migration, was compared with standard prednisone taper in the ADVOCATE trial and found noninferior to prednisone taper for the endpoint of remission—defined as a Birmingham Vasculitis Activity Score (BVAS) of 0—at week 26 and superior to prednisone taper in reaching the endpoint of sustained remission at week 52.

The GTI was used to measure glucocorticoid toxicity change in several domains, including body mass index (BMI), blood pressure, glucose tolerance, lipid metabolism, glucocorticoid myopathy, skin toxicity, neuropsychiatric effects, and infections, the authors explained in their report published in Lancet Rheumatology. During the trial GTI data were collected for each of the included domains at baseline, 13 weeks, and 26 weeks.

“We set out to do a post-hoc analysis of the ADVOCATE data to evaluate changes in individual GTI domains and their ability to differentiate treatment groups,” they wrote, by calculating the cumulative worsening score (CWS) and aggregate improvement score (AIS) for each GTI domain. The investigators also assessed the contribution to the GTI score from each domain, along with differences in the domains between the avacopan and prednisone groups seen among the 330 patients in the intent-to-treat population.

Among patients receiving avacopan (n=166) mean glucocorticoid use over 26 weeks was 1073 mg [SD 1669] vs 3192 mg [1174] in the prednisone cohort (n=165). The avacopan cohort also experienced significantly less glucocorticoid toxicity than the prednisone group by week 13 in the domains of BMI, glucose tolerance, lipid metabolism, and skin toxicity according to both the CWS and AIS. CWS values in the BMI, lipid metabolism, and skin toxicity domains remained significantly lower at 26 weeks in the avacopan group compared to the prednisone group.

“No domain favored the prednisone group for glucocorticoid toxicity reduction,” the authors reported. Of 307 patients, 280 (91%) experienced glucocorticoid toxicity at 26 weeks. Blood pressure (35% in the avacopan group vs 25% in the prednisone group), infection (22% vs 24%), and lipid metabolism (20% vs 15%) contributed the most weight toward CWS values at 26 weeks.

At 26 weeks, the investigators noted, 128 (42%) of 307 patients had combinations of improvement and worsening in different domains. “For individual patients, glucocorticoid toxicity was often nuanced, improving in some domains while worsening in others. These findings emphasize the value of a composite measure of glucocorticoid toxicity that quantifies cumulative worsening and aggregate change directly.”

—Rebecca Mashaw

Reference:

Patel NJ, Jayne DRW, Merkel PA et al. 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. Lancet Rheumatol. 2023;5(3): E130-E138

DOI: https://doi.org/10.1016/S2665-9913(23)00030-9