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Vasculitis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Michelle L. Robinette, Eli Miloslavsky, Zachary S. Wallace
One of the first studies to test the hypothesis that novel agents can substantially reduce glucocorticoid use was GiACTA. In GiACTA, tocilizumab in combination with a six-month prednisone taper was superior to a twelve-month prednisone monotherapy regimen in GCA, which was the standard at the time that the trial was designed (72). More recently, recognition that the alternative complement pathway plays an important pathogenic role in AAV has led to the investigation of avacopan, a novel C5a inhibitor, for remission induction (82). The phase 3 ADVOCATE study demonstrated that the combination of avacopan with either rituximab or cyclophosphamide and no per-protocol use of glucocorticoids after week 4 was noninferior with regard to rates of remission when compared to a standard induction regimen with a twenty-week prednisone taper (83). Furthermore, avacopan was also associated with substantially less glucocorticoid toxicity, as measured by the change in the Glucocorticoid Toxicity Index (GTI), a tool designed to prospectively capture changes in steroid toxicity. Moving forward, the GTI has the potential to comprehensively quantify the impact of new agents on morbidity related to glucocorticoids (84). The promise to drastically reduce, and even perhaps completely eliminate, glucocorticoid use in systemic vasculitides has the potential to revolutionize how we approach not only induction therapy but also maintenance of remission. The availability of a safe glucocorticoid-free regimen that acts quickly can alter the risk-benefit of chronic maintenance therapy as compared to a strategy focused on early recognition and rapid treatment of relapses.
Avacopan for the treatment of ANCA-associated vasculitis: an update
Published in Expert Review of Clinical Immunology, 2023
Mohammed Osman, Jan Willem Cohen Tervaert, Christian Pagnoux
Avacopan is one of the first agents to have achieved that key goal for the treatment of AAV to reduce GC exposure and related toxicity. Data from the CLEAR, CLASSIC, and ADVOCATE studies suggest that blocking the complement pathway may also help renal recovery to a greater extent than what was achieved with other therapeutic options available [14–16]. Avacopan was thus approved in many countries, to treat GPA and MPA, but as an adjunctive induction treatment, rather than a replacement to GC. Many physicians will likely still use some GC, and/or need time to confidently transition to GC-free regimens, and be convinced of the added clinical value of avacopan. Avacopan significantly reduced the global GC-related toxicity in the ADVOCATE trial, as it allowed for a lower cumulative use of GC, but the global infection rates were only numerically lower with avacopan compared to the standard GC regimen. The cost of the drug must also be taken into consideration and may impact on its real-world use, outside of studies. Practical recommendations from various groups are under development on how to use avacopan, taking into account the specificities (and limitations) of health-care systems in each country.
Complement profile in microscopic polyangiitis and granulomatosis with polyangiitis: analysis using sera from a nationwide prospective cohort study
Published in Scandinavian Journal of Rheumatology, 2020
S Fukui, K Ichinose, K-E Sada, J Miyamoto, M Harigai, K Amano, T Atsumi, Y Takasaki, H Dobashi, Y Arimura, H Hasegawa, Y Yuzawa, K Yamagata, N Tsuboi, S Maruyama, S Matsuo, H Makino, T Maeda, A Kawakami
There are three types of complement pathways: classical, alternative, and lectin pathways (12). Several studies have highlighted the importance of the alternative pathway in AAV in humans. The plasma levels of complement factor H were reported to be associated with disease activity measured by the Birmingham Vasculitis Activity Score (BVAS) (13). C3d and properdin staining was found in cellular crescents (14). The plasma level of Bb in patients with active AAV was significantly correlated with the proportion of total and cellular crescents in the renal biopsy specimens, the erythrocyte sedimentation rate, and the BVAS (15). These findings can explain part of the importance of the alternative pathway in AAV in humans. Jayne et al revealed that an oral C5aR1 antagonist, avacopan, was effective in replacing high-dose glucocorticoids for AAV (16). Clinical response at week 12 was achieved in over 80% of patients treated with avacopan. However, the clinical characteristics of patients with AAV who have complement activation have not been clarified.
Clinical manifestations of granulomatosis with polyangiitis: key considerations and major features
Published in Postgraduate Medicine, 2018
Bogna Grygiel-Górniak, Nattakarn Limphaibool, Katarzyna Perkowska, Mariusz Puszczewicz
Newer agents from the last decade include avacopan and campath. Campath trials have been conducted and analyzed. This human monoclonal antibody against CD-52 is responsible for lymphocyte depletion, cells responsible for triggering the initiation of the inflammation process. Thought successful in producing remission in 60% of patients, however Campath has shown not to have any supremacy in maintaining remission as 72% patients had relapsed and malignancy and thyroid disease were common adverse events [101]. Avacopan exerts its effect by selectively inhibiting the C5a receptor, thus producing a decline in the response to complement activation and further inflammation. It has been proven to induce remission in 96% of patients and successfully competing with high-dose glucocorticoid therapy, even when used alone without showing a decline in efficacy [102].