I．Introduction

Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by a small to medium-size vasculitis and the presence of circulating ANCA. Myeloperoxidase (MPO)-ANCA is the predominant serotype in MPA, while proteinase 3 (PR3)-ANCA is usually found in GPA. Based on clinical trials carried out in the 2010’s, the standard therapies for induction of remission in ANCA-associated vasculitis were high-dose glucocorticoids combined with either cyclophosphamide or rituximab^［1,2］. Similar to other countries, the 2017 Japanese guideline clearly recommended the combination of high-dose glucocorticoids and either cyclophosphamide or rituximab for first-line therapy of ANCA-associated vasculitis^［3］. Those therapies proved effective with high remission rates of around 90% in the daily clinical setting^［4,5］, although the cumulative survival rate at five years remained low at 80%^［6］. The most frequent cause of death was infections due to the immunosuppressive therapies, especially highdose glucocorticoids. In addition to infections, the glucocorticoids were associated with various side effects, such as osteoporosis, peptic ulcers, myopathy, and cataracts. Although those side effects are not related directly to mortality, they significantly decrease the quality of life of patients.

In the 2010s there was an unmet need in the clinical practice of ANCA-associated vasculitis to reduce the dose of glucocorticoids and associated side effects. As shown in Table 1, three clinical trials have been conducted recently to resolve this unmet need^［7-9］, with the guidelines having been updated based on the results of these trials.

II．The LoVAS trial

The author (SF) and his collaborators conducted the LoVAS trial^［7］, a multi-center, open-label, randomized, noninferiority clinical trial that compared the efficacy and adverse events between a reduceddose glucocorticoids plus rituximab regimen and the standard high-dose glucocorticoids plus rituximab regimen. A total of 140 Japanese patients with newly diagnosed MPA/GPA without severe glomerulonephritis (estimated glomerular filtration rate［eGFR］<15mL/min) were enrolled. In the reduced-dose glucocorticoid group, prednisolone was started at a dose of 0.5 mg/kg/day and tapered off at 5 months, whereas in the highdose glucocorticoid group, prednisolone was started at the conventional high-dose of 1.0 mg/kg/day, and then reduced to 10 mg/body/day by 5 months. Fortynine patients in the reduced-dose group (71.0%) and 45 in the high-dose group (69.2%) achieved remission at 6 months with the protocolized treatments, the primary endpoint. The difference between the two groups met the criterion for noninferiority (p<0.01 for noninferiority). In addition, the incidence of serious adverse events (SAEs) were less frequent in the reduced-dose group (18.9%) compared to that in the high-dose group (36.9%) (p=0.02). Serious infections were also significantly less frequent in the reduced-dose group (7.2%) than in the high-dose group (20.0%) (p=0.04). In summary, the new reduceddose glucocorticoid regimen in the LoVAS trial was as effective as the conventional high-dose glucocorticoid regimen and markedly reduced adverse events.

The long-term follow-up results of the LoVAS trial have recently been published^［10］. Of the patients who achieved the primary endpoint, relapse-free survival rates at 24 months were not statistically different between the reduced-dose (89.8%) and high-dose (90.5%) groups (p=0.83). However, SAEs were still less frequent in the reduced-dose group (27.5%) than in the high-dose group (46.2%) at 24 months (p=0.02). These results confirmed the long-term efficacy of the reduced-dose glucocorticoid regimen.

A limitation of the LoVAS trial was that the trial only included Japanese participants and it is well-known that there are regional differences in ANCA-associated vasculitis. Indeed, the trial participants was biased towards MPO-ANCA positivity (85.8%), a trend consistent with previously reported features of Japanese patients^［11］. Previous studies have also reported that ANCA subtypes are not associated with remission induction rates^［12-15］, while PR3-ANCA positivity is associated with a higher relapse risk compared to that of MPO-ANCA positivity^［16］. However, the reproducibility of the trial results, especially relapse, is still unclear in PR3-ANCA dominant populations such as Europe and North America.

III．The PEXIVAS trial

The PEXIVAS trial^［8］ was an international, openlabel, randomized clinical trial, which used a 2-by-2 factorial design to evaluate plasma exchange and a rapid glucocorticoid tapering regimen in newly diagnosed or relapsing MPA/GPA patients with severe glomerulonephritis (eGFR <50 mL/min). After receiving methylprednisolone pulse therapy, prednisolone was started at a dose of 1.0 mg/kg/day in both treatment groups in combination with either cyclophosphamide or rituximab (the choice was made by the local investigator before randomization). The dose of prednisolone was then tapered to 5 mg/body/day by 15 weeks in the rapid-tapering group, while prednisolone was tapered to 5 mg/body/day by 23 weeks in the standard-tapering group. In addition, patients in the plasma exchange group received plasma exchange according to the results of randomization. A total of 704 patients were enrolled in the study. The composite outcome of death or end stage kidney disease (ESKD) was the primary endpoint of the PEXIVAS trial and occurred in 27.9% of the rapid-tapering group and 25.5% of the standard-tapering group. This difference (2.3%; 90%CI, -3.4 to 8.0) between the two groups met the criterion for the noninferiority margin (11%). Although the frequency of SAEs during the overall trial period was similar between the two groups, serious infections at one year were less frequent in the rapidtapering group (27.2%) than in the standard-tapering group (33.0%) (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93). In summary, the trial demonstrated that the new rapid glucocorticoid tapering regimen had equal efficacy and better safety profiles compared to the conventional high-dose glucocorticoid regimen in MPA/GPA patients with severe glomerulonephritis.

The PEXIVAS trial also investigated whether plasma exchange influenced the composite endpoint of death and ESKD and showed that the incidence in the plasma exchange group (28.4%) was not superior to that observed in the non-plasma exchange group (31.0%) (p=0.27). However, the same research group published a meta-analysis paper on plasma exchange in ANCA-associated vasculitis^［17］, that integrated and analysed data from seven trials including 999 patients, mainly from the PEXIVAS trial. This analysis showed that plasma exchange reduced the risk of ESKD at 12 months, leading the research group to conclude that additional plasma exchange should be considered for MPA/GPA patients with severe glomerulonephritis.

IV．The ADVOCATE trial

The ADVOCATE trial^［9］ was an international, double-blind, randomized clinical trial that evaluated avacopan, a new C5a receptor inhibitor, for treatment of ANCA-associated vasculitis. A total of 331 newly diagnosed or relapsing MPA/GPA patients were enrolled. The patients received either prednisolone (initial dose of 1 mg/kg/day) or avacopan. Both treatment groups also received either cyclophosphamide or rituximab (chosen by the local investigator before randomization). In the avacopan group, less than 20 mg/day of prednisolone was allowed until 4 weeks, with the cumulative mean dose of prednisolone during the 12-month period of the trial being 1348 mg in the avacopan group and 3654 mg in the prednisolone group. The ADVOCATE trial had two primary endpoints: 1) remission at 6 months was achieved in 72.3% of the avacopan group and 70.1% of the prednisolone group (p<0.01 for noninferiority), and 2) sustained remission at 12 months, occurred in 65.7% of the avacopan group and 54.9% in the prednisolone group (p<0.01 for superiority). For safety profiles, serious infections occurred in 13.3% of the avacopan group and 15.2% of the prednisolone group. In summary, the ADVOCATE trial showed that avacopan reduced the dose of glucocorticoids for induction of remission in MPA/GPA. Although the original aim of the trial was to establish glucocorticoid-free therapy by using avacopan, the majority of the trial participants (87.3%) actually received glucocorticoids within the allowance of the trial protocol. Therefore, the clinical outcomes of glucocorticoid-free therapy with avacopan remain unclear.

V．Conclusion and perspective

The three trials described in this paper had many differences in trial design, participants, and treatment protocols. However, they shared the concept that the dose of glucocorticoids during induction of remission could be reduced compared to that used in the conventional high-dose glucocorticoid regimen. Indeed, based on the results of these three trials the updated guidelines in the 2020s recommend using the reduced-dose glucocorticoid regimen rather than the conventional high-dose glucocorticoid regimen^［18,19］. The treatment paradigm for ANCA-associated vasculitis has therefore changed, and the increased use of the new reduced-dose glucocorticoid regimens would be expected to reduce treatment-related adverse events and result in better patient outcomes.

Financial support

The author did not receive financial support relevant to this work. The content is solely the responsibility of the author.

Conflict of interest

The author reports receiving lecture fees from Chugai Pharma (Roche group), Asahi Kasei Pharma, Eisai, Daiichi Sankyo, and Kissei Pharma and a consulting fee from Asahi Kasei Pharma, all of which were unrelated to this work. No other potential conflict of interest relevant to this article is reported.

Ethical approval

Not applicable.

Data availability

Not applicable.

Acknowledgements

The author thanks Prof. Hiroshi Nakajima for critically reading this manuscript.