ANCA-associated vasculitis is a group of autoimmune diseases that cause inflammation in small blood vessels. Its two varieties are granulomatosis with polyangiitis and microscopic polyangiitis. Untreated, these conditions may lead to deadly complications such as kidney failure and lung damage. For years, the use of glucocorticoids and immunosuppressive drugs such as cyclophosphamide and rituximab was predominant in the management of AAV. Though these therapies have become life-saving, their severe side effects, particularly the long-term administration of glucocorticoids, have driven research into developing more effective and less toxic therapies. Recently, new therapies have emerged that not only reduce disease burden but also minimize treatment-related complications. Some of these emerging therapies are discussed below in the context of ANCA-associated vasculitis.
ANCA-Associated Vasculitis: Challenges in Treatment
The current therapy for AAV is high-dose glucocorticoids combined with either cyclophosphamide or rituximab. While these treatments have been helpful for most patients who went into remission, they are certainly also accompanied by severe limitations. Glucocorticoids are toxic on their own, even at low doses, with a long list of adverse effects, including infections, osteoporosis, hypertension, and diabetes. Long-term usage leads to the massive impairment of the quality of life and considerable morbidity.
Remission induction stays of old include cyclophosphamide and rituximab; however, each comes with its own complications. Cyclophosphamide is very effective but does carry with it risks to fertility, cancer, and bladder toxicity. Rituximab, the anti-CD20 monoclonal antibody, has successfully replaced cyclophosphamide for patients with relapsing disease, although with some risks too, including infections and infusion reactions. Considering these limitations, glucocorticoid-sparing treatments that provide as little use of glucocorticoids as possible coupled with more targeted and less toxic treatment alternatives are badly needed .
Avacopan: The Glucocorticoid-Sparing Agent
The most significant advancement in the AAV arena lately has been the selective avacopan, which is a C5a receptor inhibitor. C5a represents one of the most potent pro-inflammatory mediators involved with the activation of neutrophils and inflammation and destruction seen in AAV. This is manifested through the disruption of the inflammatory cascade responsible for the disease caused by decreased neutrophil activation and subsequent migration.
In a randomized controlled trial of patients with AAV, avacopan was compared with standard glucocorticoid therapy. The participants were assigned to receive either avacopan or oral prednisone in combination with standard immunosuppressive treatment with cyclophosphamide or rituximab. The two major endpoints were remission at 26 weeks and sustained remission at 52 weeks.
Remission at 26 weeks was comparable between the groups, with 72.3% of patients on avacopan achieving remission versus 70.1% on prednisone. But at 52 weeks of sustained remission, avacopan offers a very clear advantage, with 65.7% of patients on avacopan achieving sustained remission versus 54.9% on prednisone. This means avacopan spares the patients from glucocorticoid side effects and brings more sustained disease control.
The safety profile of avacopan was also favorable, with fewer serious AEs than in the prednisone group, making it a drug of choice for those intolerant to glucocorticoids or at high risk for steroid complications.