ADVOCATE and the Steroid-Sparing Era in ANCA Vasculitis

Background. ANCA-associated vasculitis was once fatal within months. Cyclophosphamide and high-dose glucocorticoids made it survivable, but treatment toxicity, especially infection, became a leading cause of early death. Neutrophil priming through the C5a receptor was identified as a driver of vascular injury, creating a target that might allow less glucocorticoid use.

What the study showed. ADVOCATE randomized patients with GPA or MPA receiving rituximab or cyclophosphamide to oral avacopan with a very short glucocorticoid course or to a standard prednisone taper. Avacopan was noninferior for remission at week 26 and superior for sustained remission at week 52. Glucocorticoid toxicity scores were lower, and kidney function recovered somewhat more in patients with renal involvement. Avacopan is FDA approved as adjunctive therapy for severe active GPA and MPA. Liver test abnormalities were the main safety signal to watch.

How it changes practice. ADVOCATE sits alongside PEXIVAS, which showed that a reduced-dose glucocorticoid schedule was as effective as standard dosing with fewer serious infections, and RAVE and MAINRITSAN, which established rituximab for induction and maintenance. Together they support a model of rituximab-based induction, lower glucocorticoid exposure and, for selected patients, avacopan. Patients with diabetes, osteoporosis, obesity or high infection risk stand to gain the most.

Open questions. Glucocorticoid exposure in the comparator arm was higher than many centers now use after PEXIVAS, so the incremental benefit over a modern reduced-dose regimen is debated. Cost and access are real barriers. We also need data on how long to continue avacopan and on its role in relapsing disease and in severe kidney involvement.