Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) includes microscopic polyangiitis (MPA), multivascular granulomatosis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Glucocorticoids plus rituximab (RTX) or cyclophosphamide (CYC) are the mainstay of treatment. Particularly for patients with severe MPA/GPA, intravenous methylprednisolone (IVMP) pulse is recommended as an induction regimen. However, there have been no head-to-head studies of pulse IVMP therapy, and its efficacy and safety are well established. Based on this, Japanese scholars conducted a real-world study to evaluate whether pulse IVMP therapy can improve the prognosis of patients with severe AAV, and to compare the efficacy and safety of two different doses of pulse IVMP regimens.
Study design
The study used observational data from the Japanese AAV Joint Registry to include patients with severe glomerulonephritis or diffuse alveolar hemorrhage between January 2017 and June 2020, and divided them into three groups: non-IVMP, IVMP 0.5 g/d pulse therapy group, and IVMP 1.0 g/d pulse therapy group. The primary outcome measure was all-cause death, with secondary outcomes including all-cause death/renal failure, severe relapse, and severe infection two to 48 weeks after treatment initiation. The Cox proportional hazards model and the Fine-Gray sub-distribution risk model were used to evaluate the treatment effect.
Findings:
1. General
The study included 201 patients, including 175 with MPA and 26 with GPA. Overall, 53 patients received IVMP 1.0 g/d pulse therapy, 50 patients received IVMP 0.5 g/d pulse therapy, and the remaining 98 patients did not receive IVMP treatment. The cumulative dose was 3075.5±484.3 mg in the IVMP 1.0 g/d group [3000 mg (92.5%) in 49 patients] and 1530±212.1 mg in the IVMP 0.5 g/day group [1500 mg (98%) in 49 patients].
2. Outcome measures
In the study, there were 6 deaths (2.8%), 4 cases (2.0%) of renal failure, 11 cases (5.3%) of severe recurrence, and 40 cases (19.8%) of severe infection.
➤ Primary outcome measures: Pulse IVMP 1.0 g/d can improve all-cause mortality in patients with severe MPA/GPA
After weighting, the mortality rate was 5.3% in the non-IVMP group and 0.4% in the IVMP 1.0 g/d group. However, pulse IVMP therapy of 0.5 g/day had no significant effect on mortality. Compared with the non-IVMP pulse therapy group, the HR of all-cause mortality was 0.46 (95%CI: 0.07~2.81) and 0.07 (95%CI: 0.01~0.41), respectively in the IVMP 0.5 g/d shock therapy group and the IVMP 1.0 g/d pulse therapy group compared with the non-IVMP pulse therapy group (Figs. 1-2).
Figure 1: Cumulative incidence curves for each outcome measure
a, all-cause death, b, a combination of all-cause death or renal failure, c, severe recurrence, d, severe infection, and c and d, death is considered a competitive risk
Fig.2 Cox proportional hazards model and Fine-Gray subdistribution risk model
Note: The risk ratios for all-cause mortality and all-cause mortality/renal failure were based on the Cox proportional hazards model, and the risk ratios for severe recurrence and severe infection were using the Fine-Gray subdistributed risk model
➤ Secondary outcome measures: The effect of two IVMP doses on all-cause death/renal failure, severe recurrence, and severe infection is uncertain
In the weighted analysis, the secondary outcomes of the IVMP 0.5 g/d pulse therapy group and the IVMP 1.0 g/d pulse therapy group compared with the non-IVMP pulse therapy group were as follows (Figures 1-2):
The HRs of all-cause death/renal failure were 1.18 (95%CI: 0.26~5.31) and 0.59 (95%CI: 0.08~4.52), respectively.
重度复发的亚分布HR分别为1.26（95%CI：0.12~13.70）和3.36（95%CI：0.49~23.29）;
The subdistributed HRs of severe infection were 1.88 (95%CI: 0.76~4.65) and 0.94 (95%CI: 0.28~3.13), respectively.
Research Discussion
The study evaluated the effect of different doses of IVMP pulse regimens on the prognosis of patients with MPA and GPA combined with severe glomerulonephritis or alveolar hemorrhage in the real world. The results showed that pulse IVMP 1.0 g/day reduced all-cause mortality compared with non-IVMP pulse therapy. In addition, the number of people required to treat to prevent one death was 20 (95% CI: 10,250). The effect of the two IVMP doses on all-cause death/renal failure, severe recurrence, and severe infection is uncertain.
The IVMP 1.0 g/d pulse group had a higher rate of severe recurrence, and the authors explained that more patients with severe disease survived in the IVMP 1.0 g/d group, resulting in an increase in the number of recurrences. Therefore, in the main analysis, we defined death as the competitive risk of severe recurrence, in addition to confounding adjustments. The results obtained suggest that IVMP had no significant effect on the risk of severe recurrence.
In addition to its effectiveness, pulse IVMP therapy can cause various adverse effects, such as the risk of serious infections and diabetes. However, in this study, no significant difference in the incidence of serious infection was found between the IVMP dose and non-IVMP groups, although the frequency of serious infections tended to be numerically higher in the IVMP 0.5 g/d group, and the differences in these results may be due to differences in the degree of confounding adjustment, unmeasured confounding, and non-IVMP treatments. For example, the IVMP 0.5 g/d group received RTX concomitant treatment slightly more frequently than the 1.0 g/d group. Therefore, in this study, it remains uncertain whether pulse IVMP therapy increases the risk of severe infection in AAV patients with similar backgrounds and treatment regimens.
Conclusions of the study
Pulse IVMP therapy at 1.0 g/d can improve all-cause mortality in patients with severe MPA/GPA, suggesting the effectiveness of pulse IVMP therapy. However, the results of this study do not clarify the optimal dose and duration of pulse IVMP therapy, and the effectiveness of pulse IVMP therapy in patients with organ involvement (eg, heart, abdomen, and nervous system) other than renal or diffuse alveolar hemorrhage (eg, cardiac, abdominal, and neurological) or life-threatening should be further studied.
Bibliography:
Omura S, Kida T, Noma H, et al. Effectiveness of intravenous methylprednisolone pulse in patients with severe microscopic polyangiitis and granulomatosis with polyangiitis. Rheumatology (Oxford). 2024 Apr 12:keae219. doi: 10.1093/rheumatology/keae219.
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