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Specks Describes Unmet Needs in Management of Granulomatosis With Polyangiitis, Microscopic Polyangiitis
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CLEVELAND — Ulrich Specks, MD, professor of medicine at the Mayo Clinic College of Medicine, described unmet needs in the management of granulomatosis with polyangiitis and microscopic polyangiitis at the Primary Vasculitides Pre-symposium of the Biologic Therapies VII Summit.
“Glucocorticoid avoidance is the primary focus of clinical research in [granulomatosis with polyangiitis] GPA and [microscopic polyangiitis] MPA,” Specks said. “Lower-dosing regimens, almost no glucocorticoids, more effective remission maintenance in order to avoid re-exposure need for remission induction therapy [and] better targeted remission regimens are all the focus of research currently.”
Specks talked about maintenance therapy for antineutrophil cytoplasmic autoantibody-associated vasculitis (ANCA-AAV), which includes — following induction with cyclophosphamide — azathioprine and methotrexate, mycophenolate mofetil and rituximab. Specks cited studies in the New England Journal of Medicine and JAMA which showed azathioprine and methotrexate were equally effective; mycophenolate mofetil can be a second-line agent and rituximab has greater efficacy than azathioprine. In one study, he said, patients with AAV who took rituximab had a relapse rate of 5% compared with 29% for patients who took azathioprine. Specks also mentioned how renal function at 6 months and renal relapse can determine long-term renal survival in patients with AAV.
Specks talked about the benefits of plasma exchange for patients with severe renal disease. In the MEPEX trial, 81% of surviving patients had used plasma exchange; whereas, 69% of the cohort in total had used it, which was a significant difference.
Specks discussed novel drugs to target innate immunity and to induce remission without glucocorticoids. One drug he mentioned, avacopan (ChemoCentryx Inc.), reportedly inhibits the complement 5a receptor. There are also drugs under investigation that inhibit formation of neutrophil extracellular traps (NETs) and drugs that inhibit ANCA target antigen activity. For NETs, Specks noted that ANCA may induce self-perpetuated NET formation. In addition, NETs can occur in AAV without infection. These can activate plasmacytoid dendritic cells through LL37. In addition, Sparks said NETs contain PR3 and MPO, in which they are accessible to ANCA. NETs bound with ANCA and can induce loss of autoantibody production. Moreover, he said S. aureus can induce NET formation and NET formation has been implicated in thrombosis.
Specks also discussed the role of B- and T-lymphocytes. He mentioned the correlation between frequency of B-cells and granulomatosis with polyangiitis (GPA) disease activity, as well as disease extent. In addition, markers of T-cell activation were able to be detected during the active disease stage of GPA, as well as in remission, he said.
“The innate immunity is the target of new drugs for remission induction,” Specks said. “Whereas, for maintenance, we still focus on targeting the adaptive immunity.” – by Will Offit
Reference:
Specks U. GPA and MPA: Future outlook. Presented at: Biologic Therapies VII Summit; April 4-8, 2017; Cleveland.
Disclosure: Specks reports he has no relevant financial disclosures.