Rituximab for Induction Therapy of ANCA-Associated Vasculitis: Practical Issues in the Asia Pacific Region

IF 2.4 4区 医学 Q2 RHEUMATOLOGY
Cheuk Man Ho, Chi Chiu Mok
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From 1995 to 2012, the European Vasculitis Society (EUVAS) conducted seven randomized controlled trials (RCTs) to evaluate the efficacy of various induction therapies in AAV, including CYC, rituximab, mycophenolate mofetil, methotrexate, azathioprine, plasmapheresis, and pulse methylprednisolone. Pooled data from 848 patients in these studies revealed an overall survival rate of 88.2% at 1 year and 78.2% at 5 years from the time of diagnosis. Compared to the general population, excess mortality by 14% at 1 year and 20% at 10 years was observed, with infections, cardiovascular complications, and malignancies being the major causes of death [<span>4</span>].</p><p>AAV exhibits notable variations in clinical manifestations between the Asian and Caucasian populations. Data from the Diagnostic and Classification Criteria in Vasculitis (DCVAS) group highlight a significantly higher proportion of anti-MPO-positive patients in the Japanese and Chinese compared to Northern Europeans (81.3% vs. 45.4% vs. 24.6%, respectively) [<span>5</span>]. Apart from the anti-MPO predominance, Asian patients are also more likely to be classified as having MPA. A collaborative epidemiological study conducted simultaneously in Japan and the United Kingdom reported a much higher incidence of MPA in Japan (annual incidence per millions of adults: 18.2 vs. 6.5 in Japan and UK, respectively) despite a similar incidence of all subtypes of AAV [<span>6</span>]. Asian AAV patients have less otorhinolaryngologic and ophthalmic involvement but more renal disease [<span>5</span>].</p><p>A difference in mortality was also observed between Asian and Caucasian patients with AAV according to real-world data. A recent study reported a high standardized mortality ratio (SMR) of MPA and GPA patients in South Korea (5.58 and 3.53, respectively) [<span>7</span>]. The all-cause-mortality risk of MPA was higher than the GPA group after adjustment for age, sex, and comorbidities (HR 1.33, <i>p</i> = 0.009). The SMR in this study is much higher than those reported in the Caucasians which range from 1.8 to 2.84 [<span>8-10</span>]. The inter-ethnic differences in clinical manifestations, treatment response, and prognosis of AAV emphasize the need for personalized approach in the management of this condition.</p><p>A combination of high-dose GCs and CYC is the conventional treatment for organ-threatening AAV. However, CYC is associated with significant adverse effects, including myelosuppression, opportunistic infection, malignancy, and infertility, and the risk increases with repeated courses of CYC, particularly in patients with relapsing disease. Rituximab, a chimeric anti-CD20 biological agent, has emerged as an alternative option for the treatment of AAV. Pivotal RCTs that include RAVE and RITUXIVAS have established non-inferiority of rituximab to CYC for induction therapy [<span>11, 12</span>]. Rituximab may be more effective in specific patient subgroups. For instance, in the RAVE study, rituximab was shown to be superior to CYC in achieving remission at month 6 in patients with relapsing disease (67% vs. 42%, <i>p</i> = 0.01). The superiority of rituximab to CYC for the primary outcome in patients with relapsing disease persisted after adjustment for ANCA subtypes (OR 1.40 [1.03–1.91]). Post hoc analysis of the same trial also revealed that anti-PR3-positive patients treated with rituximab had higher remission rate compared to CYC (65% vs. 48%, <i>p</i> = 0.04). In a retrospective study of 194 GPA patients recruited in the French Vasculitis Study Group (FVSG) registry, rituximab was shown to be better than CYC in achieving remission at month 6 (OR 1.82 [1.22–2.73]). Superiority of rituximab to CYC was also demonstrable in newly diagnosed GPA patients (<i>n</i> = 165) [<span>13</span>].</p><p>One should be reminded that, in RAVE trial, patients with alveolar hemorrhage requiring ventilatory support and advanced renal dysfunction (serum creatinine levels &gt; 4.0 mg/dL) were excluded [<span>11</span>]. As a result, the efficacy of rituximab cannot be extrapolated to this subset of patients. In a recent retrospective study from Japan involving 687 patients with life-threatening AAV (rapidly progressive glomerulonephritis and/or alveolar hemorrhage), no significant difference in in-hospital mortality between treatment with rituximab and CYC could be demonstrated (HR 1.06 [0.62–1.80]) [<span>14</span>]. Moreover, rituximab treatment was associated with a higher frequency of hemodialysis on discharge (HR 2.58 [1.02–6.91]). Thus, there is still no strong evidence to support the first-line use of rituximab in life-threatening AAV.</p><p>Major international major guidelines, including the European Alliance of Associations for Rheumatology (EULAR), American College of Rheumatology &amp; Vasculitis Foundation (ACR/VF), and Kidney Disease Improving Global Outcomes (KDIGO), recommend either rituximab or CYC as first-line options for remission induction of AAV [<span>15-17</span>]. Rituximab is favored in patients with positive anti-PR3, relapsing disease, susceptibility to opportunistic infections or malignancy, and those who wish to preserve ovarian function.</p><p>Pivotal trials evaluating rituximab in AAV, such as RAVE and RITUXIVAS, primarily involved Caucasian participants, with only one of 197 participants in the RAVE trial being Asians [<span>11, 12</span>]. As Asian patients with AAV more frequently present with renal disease, more data on the efficacy and tolerability of rituximab are needed.</p><p>In an issue of International Journal of Rheumatic Diseases, Dr. Behrooz Izadi et al. [<span>18</span>] reported retrospectively the efficacy of rituximab and CYC for remission induction in 57 Iranian patients with GPA. In two propensity score-matched groups of GPA patients, 29 patients were treated with rituximab and 28 patients were treated with CYC, in conjunction with oral prednisolone (1 mg/kg/day). At month 6, a significantly higher rate of remission was observed in the rituximab than CYC group (89.7% vs. 67.9%, <i>p</i> = 0.04). This finding aligns with the post-marketing registry study of the FVSG as forementioned [<span>13</span>]. In terms of safety profile, the infection rates were similar in both groups during the 6-month follow-up period.</p><p>It should be noted that, in the study by Behrooz et al. [<span>18</span>], 30 (52.6%) of the AAV patients were PR3-positive, 9 (15.8%) were MPO-positive, and 18 (31.6%) were ANCA-negative. The rate of PR3 positivity was remarkably lower than that of Caucasian studies, but a favorable response to rituximab was still observed. Additionally, rituximab appeared effective in the ANCA-negative AAV patient subtype, which is also consistent with previous studies [<span>19, 20</span>].</p><p>Although the data from Behrooz et al. [<span>18</span>] have provided experience of rituximab in Asian AAV patients, there are several limitations. First, the small patient cohort and retrospective design may reduce the robustness of the results. Second, the study primarily included patients with less severe disease manifestations, as evidenced by the low proportion of life-threatening or organ-threatening disease. Only four (7%) patients had renal dysfunction and none experienced alveolar hemorrhage. As a result, their data cannot support superiority of rituximab to CYC in Asian patients with more severe AAV.</p><p>The cost-effectiveness of AAV therapies is a major issue in the Asia Pacific region. The cost of rituximab and its availability in less affluent countries remains problematic. However, the recent availability of the rituximab biosimilars has significantly altered the landscape. Recent retrospective studies have shown that rituximab biosimilar are equally effective in treatment of AAV in comparison to their bio-originator [<span>21-23</span>]. Notably, the FDA has granted approval for GPA and MPA indications across all rituximab biosimilars, including Riabni, Ruxience, and Truxima [<span>24-26</span>].</p><p>Although CYC is much less expensive than rituximab, administrative cost of using CYC may be considerable. An Italian study estimated the annual health cost for an AAV patient amounted to €6168 [<span>27</span>]. Among the cost of illness, drugs cost accounted for only 27.6%, while hospitalizations and outpatient visits constituted the remaining. CYC, with its need for frequent blood monitoring and inherent infection risk, may inadvertently contribute to higher overall healthcare costs due to intensive management of associated adverse events. This observation is confirmed by a recent UK study which showed a substantially higher administrative cost of CYC than rituximab in the treatment of AAV [<span>28</span>]. The total visit cost for CYC was higher than rituximab biosimilar (£44 000 vs. £14 000). The excess cost related to CYC was attributed to factors such as more frequent day unit admissions, consultant visits, and multidisciplinary team reviews preceding each infusion, and extra cost from blood monitoring and management of adverse events.</p><p>In summary, rituximab has been shown to be non-inferior to CYC in the treatment of AAV. Rituximab may be superior to CYC in patients with relapsing disease and those with PR3-ANCA subtype. The study by Behrooz et al. [<span>18</span>] has provided some reassuring data regarding the efficacy and safety of rituximab in Asian patients with AAV. However, their study had involved a very small proportion of patients with severe life-threatening disease. Therefore, there is still lack of strong evidence of the upfront use of rituximab in AAV patients with rapidly progressive glomerulonephritis and alveolar hemorrhage. With the availability of rituximab biosimilars, it is expected that more patients will be treated upfront with this biologic in AAV patients. CYC may better be reserved for those patients who present with life/organ-threatening disease. Further collaborative studies are warranted to study the efficacy of newer treatment modalities of AAV in the APLAR region.</p><p>The authors take full responsibility for this article.</p><p>The authors declare no conflicts of interest.</p>","PeriodicalId":14330,"journal":{"name":"International Journal of Rheumatic Diseases","volume":"27 12","pages":""},"PeriodicalIF":2.4000,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/1756-185X.70016","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Rheumatic Diseases","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/1756-185X.70016","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

ANCA-associated vasculitis (AAV), comprising granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA), represents a group of small to medium vessel vasculitides that may affect multiple organ systems, leading to vascular-mediated damage, organ failure, and mortality. Untreated AAV patients have a 1-year mortality of up to 80% [1]. The introduction of glucocorticoids (GCs) and cyclophosphamide (CYC) as induction therapy in the 1960s has significantly improved the prognosis [2]. In the landmark CYCLOPS trial published in 2009, the mortality of AAV patients treated with GCs and CYC at month 18 was 9% [3]. From 1995 to 2012, the European Vasculitis Society (EUVAS) conducted seven randomized controlled trials (RCTs) to evaluate the efficacy of various induction therapies in AAV, including CYC, rituximab, mycophenolate mofetil, methotrexate, azathioprine, plasmapheresis, and pulse methylprednisolone. Pooled data from 848 patients in these studies revealed an overall survival rate of 88.2% at 1 year and 78.2% at 5 years from the time of diagnosis. Compared to the general population, excess mortality by 14% at 1 year and 20% at 10 years was observed, with infections, cardiovascular complications, and malignancies being the major causes of death [4].

AAV exhibits notable variations in clinical manifestations between the Asian and Caucasian populations. Data from the Diagnostic and Classification Criteria in Vasculitis (DCVAS) group highlight a significantly higher proportion of anti-MPO-positive patients in the Japanese and Chinese compared to Northern Europeans (81.3% vs. 45.4% vs. 24.6%, respectively) [5]. Apart from the anti-MPO predominance, Asian patients are also more likely to be classified as having MPA. A collaborative epidemiological study conducted simultaneously in Japan and the United Kingdom reported a much higher incidence of MPA in Japan (annual incidence per millions of adults: 18.2 vs. 6.5 in Japan and UK, respectively) despite a similar incidence of all subtypes of AAV [6]. Asian AAV patients have less otorhinolaryngologic and ophthalmic involvement but more renal disease [5].

A difference in mortality was also observed between Asian and Caucasian patients with AAV according to real-world data. A recent study reported a high standardized mortality ratio (SMR) of MPA and GPA patients in South Korea (5.58 and 3.53, respectively) [7]. The all-cause-mortality risk of MPA was higher than the GPA group after adjustment for age, sex, and comorbidities (HR 1.33, p = 0.009). The SMR in this study is much higher than those reported in the Caucasians which range from 1.8 to 2.84 [8-10]. The inter-ethnic differences in clinical manifestations, treatment response, and prognosis of AAV emphasize the need for personalized approach in the management of this condition.

A combination of high-dose GCs and CYC is the conventional treatment for organ-threatening AAV. However, CYC is associated with significant adverse effects, including myelosuppression, opportunistic infection, malignancy, and infertility, and the risk increases with repeated courses of CYC, particularly in patients with relapsing disease. Rituximab, a chimeric anti-CD20 biological agent, has emerged as an alternative option for the treatment of AAV. Pivotal RCTs that include RAVE and RITUXIVAS have established non-inferiority of rituximab to CYC for induction therapy [11, 12]. Rituximab may be more effective in specific patient subgroups. For instance, in the RAVE study, rituximab was shown to be superior to CYC in achieving remission at month 6 in patients with relapsing disease (67% vs. 42%, p = 0.01). The superiority of rituximab to CYC for the primary outcome in patients with relapsing disease persisted after adjustment for ANCA subtypes (OR 1.40 [1.03–1.91]). Post hoc analysis of the same trial also revealed that anti-PR3-positive patients treated with rituximab had higher remission rate compared to CYC (65% vs. 48%, p = 0.04). In a retrospective study of 194 GPA patients recruited in the French Vasculitis Study Group (FVSG) registry, rituximab was shown to be better than CYC in achieving remission at month 6 (OR 1.82 [1.22–2.73]). Superiority of rituximab to CYC was also demonstrable in newly diagnosed GPA patients (n = 165) [13].

One should be reminded that, in RAVE trial, patients with alveolar hemorrhage requiring ventilatory support and advanced renal dysfunction (serum creatinine levels > 4.0 mg/dL) were excluded [11]. As a result, the efficacy of rituximab cannot be extrapolated to this subset of patients. In a recent retrospective study from Japan involving 687 patients with life-threatening AAV (rapidly progressive glomerulonephritis and/or alveolar hemorrhage), no significant difference in in-hospital mortality between treatment with rituximab and CYC could be demonstrated (HR 1.06 [0.62–1.80]) [14]. Moreover, rituximab treatment was associated with a higher frequency of hemodialysis on discharge (HR 2.58 [1.02–6.91]). Thus, there is still no strong evidence to support the first-line use of rituximab in life-threatening AAV.

Major international major guidelines, including the European Alliance of Associations for Rheumatology (EULAR), American College of Rheumatology & Vasculitis Foundation (ACR/VF), and Kidney Disease Improving Global Outcomes (KDIGO), recommend either rituximab or CYC as first-line options for remission induction of AAV [15-17]. Rituximab is favored in patients with positive anti-PR3, relapsing disease, susceptibility to opportunistic infections or malignancy, and those who wish to preserve ovarian function.

Pivotal trials evaluating rituximab in AAV, such as RAVE and RITUXIVAS, primarily involved Caucasian participants, with only one of 197 participants in the RAVE trial being Asians [11, 12]. As Asian patients with AAV more frequently present with renal disease, more data on the efficacy and tolerability of rituximab are needed.

In an issue of International Journal of Rheumatic Diseases, Dr. Behrooz Izadi et al. [18] reported retrospectively the efficacy of rituximab and CYC for remission induction in 57 Iranian patients with GPA. In two propensity score-matched groups of GPA patients, 29 patients were treated with rituximab and 28 patients were treated with CYC, in conjunction with oral prednisolone (1 mg/kg/day). At month 6, a significantly higher rate of remission was observed in the rituximab than CYC group (89.7% vs. 67.9%, p = 0.04). This finding aligns with the post-marketing registry study of the FVSG as forementioned [13]. In terms of safety profile, the infection rates were similar in both groups during the 6-month follow-up period.

It should be noted that, in the study by Behrooz et al. [18], 30 (52.6%) of the AAV patients were PR3-positive, 9 (15.8%) were MPO-positive, and 18 (31.6%) were ANCA-negative. The rate of PR3 positivity was remarkably lower than that of Caucasian studies, but a favorable response to rituximab was still observed. Additionally, rituximab appeared effective in the ANCA-negative AAV patient subtype, which is also consistent with previous studies [19, 20].

Although the data from Behrooz et al. [18] have provided experience of rituximab in Asian AAV patients, there are several limitations. First, the small patient cohort and retrospective design may reduce the robustness of the results. Second, the study primarily included patients with less severe disease manifestations, as evidenced by the low proportion of life-threatening or organ-threatening disease. Only four (7%) patients had renal dysfunction and none experienced alveolar hemorrhage. As a result, their data cannot support superiority of rituximab to CYC in Asian patients with more severe AAV.

The cost-effectiveness of AAV therapies is a major issue in the Asia Pacific region. The cost of rituximab and its availability in less affluent countries remains problematic. However, the recent availability of the rituximab biosimilars has significantly altered the landscape. Recent retrospective studies have shown that rituximab biosimilar are equally effective in treatment of AAV in comparison to their bio-originator [21-23]. Notably, the FDA has granted approval for GPA and MPA indications across all rituximab biosimilars, including Riabni, Ruxience, and Truxima [24-26].

Although CYC is much less expensive than rituximab, administrative cost of using CYC may be considerable. An Italian study estimated the annual health cost for an AAV patient amounted to €6168 [27]. Among the cost of illness, drugs cost accounted for only 27.6%, while hospitalizations and outpatient visits constituted the remaining. CYC, with its need for frequent blood monitoring and inherent infection risk, may inadvertently contribute to higher overall healthcare costs due to intensive management of associated adverse events. This observation is confirmed by a recent UK study which showed a substantially higher administrative cost of CYC than rituximab in the treatment of AAV [28]. The total visit cost for CYC was higher than rituximab biosimilar (£44 000 vs. £14 000). The excess cost related to CYC was attributed to factors such as more frequent day unit admissions, consultant visits, and multidisciplinary team reviews preceding each infusion, and extra cost from blood monitoring and management of adverse events.

In summary, rituximab has been shown to be non-inferior to CYC in the treatment of AAV. Rituximab may be superior to CYC in patients with relapsing disease and those with PR3-ANCA subtype. The study by Behrooz et al. [18] has provided some reassuring data regarding the efficacy and safety of rituximab in Asian patients with AAV. However, their study had involved a very small proportion of patients with severe life-threatening disease. Therefore, there is still lack of strong evidence of the upfront use of rituximab in AAV patients with rapidly progressive glomerulonephritis and alveolar hemorrhage. With the availability of rituximab biosimilars, it is expected that more patients will be treated upfront with this biologic in AAV patients. CYC may better be reserved for those patients who present with life/organ-threatening disease. Further collaborative studies are warranted to study the efficacy of newer treatment modalities of AAV in the APLAR region.

The authors take full responsibility for this article.

The authors declare no conflicts of interest.

利妥昔单抗诱导治疗anca相关血管炎:亚太地区的实际问题。
anca相关性血管炎(AAV),包括肉芽肿病合并多血管炎(GPA)、显微多血管炎(MPA)和嗜酸性肉芽肿病合并多血管炎(EGPA),代表了一组可影响多器官系统的中小型血管血管,导致血管介导的损伤、器官衰竭和死亡。未经治疗的AAV患者1年死亡率高达80%。20世纪60年代引入糖皮质激素(GCs)和环磷酰胺(CYC)作为诱导治疗,显著改善了预后[2]。在2009年发表的具有里程碑意义的CYCLOPS试验中,接受GCs和CYC治疗的AAV患者在第18个月的死亡率为9%。1995年至2012年,欧洲血管炎学会(EUVAS)开展了7项随机对照试验(rct),评估各种诱导治疗AAV的疗效,包括CYC、利妥昔单抗、霉酚酸酯、甲氨蝶呤、硫唑嘌呤、血浆置换、脉冲甲基强的松龙。这些研究中来自848名患者的汇总数据显示,自诊断后1年和5年的总生存率分别为88.2%和78.2%。与一般人群相比,1年死亡率高出14%,10年死亡率高出20%,其中感染、心血管并发症和恶性肿瘤是死亡的主要原因。AAV在亚洲和高加索人群的临床表现有显著差异。来自血管炎诊断和分类标准(DCVAS)组的数据强调,与北欧相比,日本和中国的抗mpo阳性患者比例明显更高(分别为81.3%、45.4%和24.6%)。除了抗mpo的优势,亚洲患者也更有可能被归类为MPA。在日本和英国同时进行的一项合作流行病学研究报告称,尽管所有AAV亚型bbb的发病率相似,但日本的MPA发病率要高得多(每百万成年人的年发病率:18.2 vs.日本和英国分别为6.5)。亚洲AAV患者的耳鼻喉及眼部病变较少,但肾脏病变较多。根据实际数据,亚洲和高加索AAV患者的死亡率也存在差异。最近的一项研究报告称,韩国MPA和GPA患者的标准化死亡率(SMR)很高(分别为5.58和3.53)。经年龄、性别和合并症校正后,MPA组的全因死亡风险高于GPA组(HR 1.33, p = 0.009)。本研究的SMR远高于白种人的报道,其范围为1.8 ~ 2.84[8-10]。AAV在临床表现、治疗反应和预后方面的种族差异强调了对这种疾病进行个性化治疗的必要性。高剂量GCs和CYC联合治疗是威胁器官的AAV的常规治疗方法。然而,CYC与显著的不良反应相关,包括骨髓抑制、机会性感染、恶性肿瘤和不孕症,并且随着CYC疗程的重复,风险增加,特别是在疾病复发的患者中。利妥昔单抗是一种嵌合抗cd20生物制剂,已成为治疗AAV的另一种选择。包括RAVE和RITUXIVAS在内的关键随机对照试验已经建立了利妥昔单抗对CYC诱导治疗的非劣效性[11,12]。利妥昔单抗可能对特定患者亚组更有效。例如,在RAVE研究中,利妥昔单抗在复发疾病患者第6个月获得缓解方面优于CYC(67%对42%,p = 0.01)。调整ANCA亚型后,在复发性疾病患者的主要结局方面,利妥昔单抗优于CYC (OR为1.40[1.03-1.91])。同一试验的事后分析还显示,与CYC相比,接受利妥昔单抗治疗的抗pr3阳性患者的缓解率更高(65%对48%,p = 0.04)。在法国血管炎研究组(FVSG)注册的194例GPA患者的回顾性研究中,利妥昔单抗在第6个月达到缓解的效果优于CYC (OR为1.82[1.22-2.73])。在新诊断的GPA患者(n = 165)中,利妥昔单抗优于CYC。需要提醒的是,在RAVE试验中,需要通气支持的肺泡出血和晚期肾功能不全(血清肌酐水平4.0 mg/dL)的患者被排除在外。因此,利妥昔单抗的疗效不能推断到这部分患者。在日本最近一项涉及687例危及生命的AAV(快速进展性肾小球肾炎和/或肺泡出血)患者的回顾性研究中,可以证明利美昔单抗和CYC治疗在住院死亡率方面没有显著差异(HR 1.06[0.62-1.80])。 因此,对于伴有快速进展性肾小球肾炎和肺泡出血的AAV患者,尚缺乏利妥昔单抗前期应用的有力证据。随着利妥昔单抗生物类似药的出现,预计更多的AAV患者将接受这种生物类似药的前期治疗。CYC最好留给那些患有危及生命/器官疾病的患者。需要进一步的合作研究来研究AAV在APLAR地区的新治疗方式的疗效。作者对本文负全部责任。作者声明无利益冲突。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
3.70
自引率
4.00%
发文量
362
审稿时长
1 months
期刊介绍: The International Journal of Rheumatic Diseases (formerly APLAR Journal of Rheumatology) is the official journal of the Asia Pacific League of Associations for Rheumatology. The Journal accepts original articles on clinical or experimental research pertinent to the rheumatic diseases, work on connective tissue diseases and other immune and allergic disorders. The acceptance criteria for all papers are the quality and originality of the research and its significance to our readership. Except where otherwise stated, manuscripts are peer reviewed by two anonymous reviewers and the Editor.
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