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Alveolar Hemorrhage in ANCA-associated Vasculitis: Results of an International, Randomized, Controlled Trial (PEXIVAS)
Fussner, L. A., Flores-Suárez, L. F., Cartin-Ceba, R., Specks, U., Cox, P. G., Jayne, D. R. W., Merkel, P. A., Walsh M Md, PhD
American journal of respiratory and critical care medicine. 2024
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Editor's Choice
Abstract
RATIONALE Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The Plasma Exchange (PLEX) and Glucocorticoids (GC) in Severe AAV (PEXIVAS;NCT00987389) trial was the largest in AAV and first to enroll participants with DAH requiring mechanical ventilation. OBJECTIVES Evaluate characteristics, treatment effects, outcomes for patients with AAV with and without DAH. METHODS PEXIVAS randomized 704 participants to PLEX or no-PLEX and reduced or standard-dose GC. DAH status was defined at enrollment as no-DAH, non-severe, or severe (room air SpO(2)≤85% or use of mechanical ventilation). MEASUREMENTS AND MAIN RESULTS At enrollment, 191(27.1%) participants had DAH (61 severe, including 29 ventilated) and were younger, more frequently relapsing, PR3-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH (n=513,72.9%). Among those with DAH, 8/95(8.4%) receiving PLEX died within one year vs. 15/96(15.6%) with no-PLEX (HR 0.52,CI 0.21-1.24), while 13/96(13.5%) receiving reduced-GC died vs. 10/95(10.5%) with standard-GC (HR 1.33,CI 0.57-3.13). When ventilated, ventilator-free days were similar with PLEX vs. no-PLEX (medians 25,IQR 22-26 vs. 22-27), fewer with reduced-GC (23[20-25]) vs. standard-GC (26[25-28]). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191(12.0%) with DAH died within one year vs. 34/513(6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments. CONCLUSION Patients with AAV and DAH differ from those without DAH in multiple ways. Further data are required to confirm or refute a benefit of PLEX or GC dosing on mortality. Clinical trial registration available at www. CLINICALTRIALS gov, ID: NCT00987389.
PICO Summary
Population
Patients with severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis including glomerulonephritis and/or diffuse alveolar hemorrhage (DAH), enrolled in the PEXIVAS trial (n= 704).
Intervention
Plasma exchange (PLEX) and standard glucocorticoid (GC) (n= 176). PLEX and reduced GC (n= 176).
Comparison
No PLEX and standard GC (n= 175). No PLEX and reduced GC (n= 177).
Outcome
At enrollment, 191 (27.1%) participants had DAH and were younger, more frequently relapsing, proteinase 3-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH (n= 513 (72.9%)). Among those with DAH, 8/95 (8.4%) receiving PLEX died within one year vs. 15/96 (15.6%) with no-PLEX (HR 0.52; CI [0.21, 1.24]), while 13/96 (13.5%) receiving reduced-GC died vs. 10/95 (10.5%) with standard-GC (HR 1.33; CI [0.57, 3.13]). When ventilated, ventilator-free days were similar with PLEX vs. no-PLEX (medians 25; IQR 22, 26 vs. 22, 27), fewer with reduced-GC (23 [20, 25]) vs. standard-GC (26 [25, 28]). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within one year vs. 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments.
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Plasma exchange for acute optic neuritis in neuromyelitis optica or neuromyelitis optica spectrum disorder: a systematic review
Naphattalung, Y., Chuenkongkaew, W. L., Chirapapaisan, N., Laowanapiban, P., Sawangkul, S.
Annals of medicine. 2023;55(1):2227422
Abstract
OBJECTIVES To appraise whether plasma exchange (PLEX) effectively improves visual function for acute optic neuritis (ON) in neuromyelitis optica (NMO) or neuromyelitis optica spectrum disorder (NMOSD). METHODS AND ANALYSIS We searched Medline, Embase, Cochrane Library, ProQuest Central, and Web of Science to identify relevant articles published between 2006 and 2020.Eligible studies were in English and evaluated visual outcomes for people with acute ON in NMO or NMOSD treated with PLEX. They also had adequate pre- and posttreatment data. Excluded were studies with 1 or 2 case reports, or incomplete data. RESULTS Twelve studies were qualitatively synthesized (1 RCT; 1 controlled NRSI; 10 observational studies). Five before-and-after observational studies were used for quantitative synthesis. The PLEX in the 5 studies (3 to 7 cycles over 2 to 3 weeks) was performed as second-line or adjunctive therapy for acute ON in NMO/NMOSD.The qualitative synthesis revealed that visual-acuity recovery occurred between one day and 6 months after the first PLEX cycle completion. Thirty-two of 48 participants in the 5 quantitative-synthesis studies received PLEX. Relative to pre-PLEX values, visual-acuity improvements were nonsignificant at these post-PLEX time points: 1 day (SMD 0.611; 95% CI -0.620 to 1.842); 2 weeks (SMD 0.0214; 95% CI -1.250 to 1.293); 3 months (SMD 1.014; 95% CI -0.954 to 2.982); and 6 months (SMD 0.450; 95% CI -2.643 to 3.543). CONCLUSIONS There were inadequate data to determine whether PLEX effectively treats acute ON in NMO/NMOSD. Aggregate current data of this systematic review is insufficient to definitively conclude whether therapeutic PLEX is effective in improving VA in cases of NMO or NMOSD. eng
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Plasma exchange and glucocorticoids to delay death or end-stage renal disease in anti-neutrophil cytoplasm antibody-associated vasculitis: PEXIVAS non-inferiority factorial RCT
Jayne, D., Walsh, M., Merkel, P. A., Peh, C. A., Szpirt, W., Puéchal, X., Fujimoto, S., Hawley, C., Khalidi, N., Jones, R., et al
Health Technology Assessment (Winchester, England). 2022;26(38):1-60
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Editor's Choice
Abstract
BACKGROUND Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes. OBJECTIVES We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease. DESIGN This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab. SETTING Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated. PARTICIPANTS Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of < 50 ml/minute/1.73 m(2) or diffuse alveolar haemorrhage attributable to active anti-neutrophil cytoplasm antibody-associated vasculitis. INTERVENTIONS Participants received seven sessions of plasma exchange within 14 days or no plasma exchange. Oral glucocorticoids commenced with prednisolone 1 mg/kg/day and were reduced over different lengths of time to 5 mg/kg/day, such that cumulative oral glucocorticoid exposure in the first 6 months was 50% lower in patients allocated to the reduced-dose regimen than in those allocated to the standard-dose regimen. All patients received the same glucocorticoid dosing from 6 to 12 months. Subsequent dosing was at the discretion of the treating physician. PRIMARY OUTCOME The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial. RESULTS The study recruited 704 patients from June 2010 to September 2016. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86, 95% confidence interval 0.65 to 1.13; p = 0.3). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023, 95% confidence interval 0.034 to 0.08; p = 0.5), thus meeting our non-inferiority hypothesis. Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% confidence interval 0.52 to 0.93; p = 0.016). CONCLUSIONS Plasma exchange did not prolong the time to death and/or end-stage renal disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis with severe renal or pulmonary involvement. A reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen and was associated with fewer serious infections. FUTURE WORK A meta-analysis examining the effects of plasma exchange on kidney outcomes in anti-neutrophil cytoplasm antibody-associated vasculitis is planned. A health-economic analysis of data collected in this study to examine the impact of both plasma exchange and reduced glucocorticoid dosing is planned to address the utility of plasma exchange for reducing early end-stage renal disease rates. Blood and tissue samples collected in the study will be examined to identify predictors of response to plasma exchange in anti-neutrophil cytoplasm in antibody-associated vasculitis. The benefits associated with reduced glucocorticoid dosing will inform future studies of newer therapies to permit further reduction in glucocorticoid exposure. Data from this study will contribute to updated management recommendations for anti-neutrophil cytoplasm antibody-associated vasculitis. LIMITATIONS This study had an open-label design which may have permitted observer bias; however, the nature of the end points, end-stage renal disease and death, would have minimised this risk. Despite being, to our knowledge, the largest ever trial in anti-neutrophil cytoplasm antibody-associated vasculitis, there was an insufficient sample size to assess clinically useful benefits on the separate components of the primary end-point: end-stage renal disease and death. Use of a fixed-dose plasma exchange regimen determined by consensus rather than data-driven dose ranging meant that some patients may have been underdosed, thus reducing the therapeutic impact. In particular, no biomarkers have been identified to help determine dosing in a particular patient, although this is one of the goals of the biomarker plan of this study. TRIAL REGISTRATION This trial is registered as ISRCTN07757494, EudraCT 2009-013220-24 and Clinicaltrials.gov NCT00987389. FUNDING This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 38. See the NIHR Journals Library website for further project information.
PICO Summary
Population
Patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis, enrolled in the Plasma Exchange In VASculitis (PEXIVAS) trial in 95 hospitals in Europe, North America, Australia/New Zealand and Japan (n= 704).
Intervention
[Two-by-two factorial design] Adjunctive plasma exchange (n= 352). Reduced glucocorticoid dosing regimen (n= 353).
Comparison
No plasma exchange (n= 352). Standard glucocorticoid dosing regimen (n= 351).
Outcome
The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86; 95% confidence interval (CI) [0.65, 1.13]). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023; 95% CI [0.034, 0.08]). Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% CI [0.52, 0.93]).
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Efficacy and safety of plasma exchange or immunoadsorption for the treatment of option neuritis in demyelinating diseases: A systematic review and meta-analysis
Zhang, J., Fan, A., Wei, L., Wei, S., Xie, L., Li, M., Zhang, W., Liu, Q., Yang, K.
European Journal of Ophthalmology. 2022;32(4):1857-1871
Abstract
BACKGROUND There are no systematic reviews yet that evaluated the effects of PE/IA in patients with optic neuritis (ON) in demyelinating diseases. A meta-analysis of available study is needed to further explore the value of plasma exchange (PE) or immunoadsorption (IA) in treating ON in demyelinating diseases. METHODS All relevant articles published on PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), VIP Database, Wanfang, Sinomed and ophthalmology professional websites were searched. Study characteristics, demographic characteristics, clinical features and outcome measures were extracted. Response rate, adverse events (AE) rate, serious adverse event (SAE) rate, the log of the minimum angle of resolution (logMAR), visual outcome scale (VOS) and expanded disability status scales (EDSS) were evaluated using a random-effects model. RESULTS 35 studies were included between 1985 and 2020, containing 1191 patients. The response rates of PE and IA in acute attack of ON were 68% and 82% respectively. LogMAR (-0.60 to - 1.42) and VOS (-1.10 to -1.82) had been significantly improved from within 1 month to more than 1 month after PE treatment. Besides, we found that logMAR improved 1.78, 0.95 and 0.38, respectively ,when the time from symptom onset to the first PE/IA was less than 21 days, 21-28 days, and more than 28 days. The pooled mean difference of EDSS was -1.14.Adverse effects rate in patients with PE or IA were 0.20 and 0.06, respectively. CONCLUSION The meta-analysis provided evidence that PE/IA treatment was an effective and safe intervention, and it is recommended that early initiation of PE/IA treatment is critical.
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Efficacy and safety of double-filtration plasmapheresis treatment of myasthenia gravis: A systematic review and meta-analysis
Liu C, Liu P, Ma M, Yang H, Qi G
Medicine. 2021;100(17):e25622
Abstract
OBJECTIVES To evaluate the efficacy of double-filtration plasmapheresis (DFPP) treatment of myasthenia gravis (MG) through a systematic review and meta-analysis. METHODS PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), and Wanfang databases were searched for randomized controlled trials (RCTs) and clinical controlled trials (CCTs) on DFPP for MG from database establishment to June 2019. Two researchers independently screened the articles, extracted the data, and cross checked the results. RevMan 5.3 was used for statistical analyses. RESULTS Seven RCTs and 2 CCTs were found comprising 329 patients. The results showed that clinical MG remission rate after DFPP treatment was significantly higher (OR = 4.33; 95% confidence interval [CI], 1.97-9.53; P < .001) and the serum levels of antititin antibody was significantly decreased (standardized mean difference [SMD] = 9.30; 95% CI, 7.51-11.08; P < .001). In addition, the quantitative MG (QMG) score, hospital stay and time to remission of MG symptoms, and acetylcholine receptor antibody (AchRAb) decreased in the DFPP treatment group; however, these outcomes had high heterogeneity among the studies. Only one study has reported on the adverse effects, including hypotension and hematoma. CONCLUSION This meta-analysis suggests that DFPP can be recommended for the short-term mitigation of MG. Because our review was limited by the quantity and quality of the included studies, the above conclusions should be verified by additional high-quality studies.
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Immunoadsorption and plasma exchange-Efficient treatment options for neurological autoimmune diseases
Boedecker SC, Luessi F, Engel S, Kraus D, Klimpke P, Holtz S, Meinek M, Marczynski P, Weinmann A, Weinmann-Menke J
Journal of clinical apheresis. 2021
Abstract
BACKGROUND Therapeutic plasma exchange (TPE) and immunoadsorption (IA) are first or second line treatment options in patients with neurological autoimmune diseases, including multiple sclerosis, neuromyelitis optica spectrum disorders (NMSOD), chronic inflammatory demyelinating polyneuropathy, acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré syndrome), and autoimmune encephalitis. METHODS In this prospective randomized controlled monocentric study, we assessed safety and efficacy of therapy with IA or TPE in patients with neurological autoimmune diseases. Treatment response was assessed using various neurological scores as well by measuring immunoglobulin and cytokine concentrations. Clinical outcome was evaluated by application of specific scores for the underlying diseases. RESULTS A total of 32 patients were analyzed. Among these, 19 patients were treated with TPE and 13 patients with IA. IA and TPE therapy showed a comparable significant treatment response. In patients with MS and NMOSD, mean EDSS before and after treatment showed a significant reduction after treatment with IA. We observed a significant reduction of the pro-inflammatory cytokines IL-12, lL-17, IL-6, INF-γ, and tumor necrosis factor alpha during IA treatment, whereas this reduction was not seen in patients treated with TPE. CONCLUSIONS In summary, both IA and TPE were effective and safe procedures for treating neurological autoimmune diseases. However, there was a trend towards longer therapy response in patients treated with IA compared to TPE, possibly related to a reduction in plasma levels of pro-inflammatory cytokines seen only in the IA-treated group.
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Therapeutic Plasma Exchange in Myasthenia Gravis: A Systematic Literature Review and Meta-Analysis of Comparative Evidence
Ipe, T. S., Davis, A. R., Raval, J. S.
Frontiers in Neurology. 2021;12:662856
Abstract
Background: Patients with Myasthenia Gravis (MG) can be treated acutely with therapeutic plasma exchange (TPE) or intravenous immune globulin (IVIG). To date, there is no definitive understanding of which of the two treatments is more effective and safer. The purpose of this study was to systematically review the literature on the comparative efficacy and safety of TPE to other available treatments for MG. Methods: A systematic literature search for studies published between 1997 and 2017 was performed per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using two database sources, MEDLINE (through the PubMed database) and Cochrane Library. Results: The search strategy resulted in 535 articles whose abstracts were reviewed. Among these, 165 full texts articles were reviewed for eligibility and 101 articles were excluded. Of the 165 articles, 64 articles were included for a systematic literature and 11 articles for a meta-analysis. Conclusions: This systematic literature review and meta-analysis of treatment options showed that there was a higher response rate with TPE than IVIG in acute MG patients and patients undergoing thymectomy. There was no difference in mortality between the two treatment options. Our findings highlight the need for additional randomized clinical trials in these patients with MG.
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The therapeutic effect of plasma exchange on ANCA-associated vasculitis: A meta-analysis
Zhu Y, Rao J, Liu L, Ou J, Li W, Xue C
Clinical nephrology. 2021
Abstract
AIMS: The therapeutic effect of plasma exchange (PLEX) combined with conventional treatment in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) remains controversial. MATERIALS AND METHODS We searched PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure for randomized controlled trials (RCTs) and cohort studies that compared PLEX added to conventional therapy with conventional therapy only in active AAV. RESULTS 19 studies were included for the meta-analysis. Compared with the conventional therapy group, the PLEX group had a significantly reduced risk of end-stage renal disease (ESRD) at 3 months (odds ratio (OR) = 0.32, 95% confidence interval (CI) = 0.16 - 0.66, p = 0.002, I2 = 0%), and the ANCA titerwas also decreased (OR = 40.99, 95% Cl = 23.56 - 58.43, p < 0.00001, I2 = 42%). The plasma and non-plasma exchange groups had no substantial differences in terms of short- and long-term outcomes, including all-cause mortality, ESRD risk at 12 months and 5 years, remission rate, serum creatine levels, or serious adverse events. CONCLUSION PLEX therapy was not associated with favorable long-term outcomes, although the results showed benefits in the incidence of ESRD rate at 3 months and ANCA titers in patients with AAV. No advantage of PLEX added to conventional therapy on mortality and complete remission was observed in patients with diffuse alveolar hemorrhage. Further high-quality multicenter RCTs with a high number of participants are required to assess the potential efficacy of PLEX in active AAV.
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Efficacy of plasma exchange for antineutrophil cytoplasmic antibody-associated systemic vasculitis: a systematic review and meta-analysis
Yamada Y, Harada M, Hara Y, Iwabuchi R, Hashimoto K, Yamamoto S, Kamijo Y
Arthritis research & therapy. 2021;23(1):28
Abstract
OBJECTIVE To assess through systematic review and meta-analysis whether plasma exchange (PE) is associated with prognosis in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients. METHODS A systematic search of PubMed, MEDLINE, Embase, and CENTRAL databases from inception to 17 June 2020 was conducted. Ongoing or unpublished trials were also searched in ClinicalTrials.gov and the World Health Organization trials portal. Randomised controlled trials (RCTs) comparing PE vs. non-PE in AAV patients (microscopic polyangiitis [MPA], granulomatosis with polyangiitis [GPA], or eosinophilic granulomatosis with polyangiitis [EGPA]) were included. The combined risk ratio (RR) was calculated by the random-effects model using the Mantel-Haenszel method. Heterogeneity was measured using the I(2) statistic. Primary outcomes were mortality, clinical remission (CR), and adverse events (AEs). RESULTS Four RCTs comparing PE vs. no PE (N = 827) and 1 RCT comparing PE vs. pulse steroid treatment (N = 137) were included. All participants were MPA or GPA patients (no EGPA patients). PE was not associated with main primary outcomes compared with no PE (mortality RR 0.93 [95% confidence interval {CI} 0.70-1.24], I(2) = 0%; CR RR 1.02 [95% CI 0.91-1.15], I(2) = 0%; and AE RR 1.10 [95% CI 0.73-1.68], I(2) = 37%) or pulse steroid (mortality RR 0.99 [95% CI 0.71-1.37]; CR [the Birmingham Vasculitis Activity score] mean difference - 0.53 [95% CI - 1.40-0.34]; and AE RR 1.05 [95% CI 0.74-1.48]). Focusing on the early treatment phases, PE was associated with a reduction in end-stage renal disease incidence compared with both no PE (PE 1/43 vs. no PE 10/41; RR 0.14 [0.03-0.77] at 3 months) and pulse steroid (PE 11/70 vs. pulse steroid 23/67; RR 0.46 [0.24-0.86] at 3 months). CONCLUSION We carried out a systematic review and meta-analysis targeting all AAV patients, including MPA, GPA, and EGPA. In AAV patients, performing PE was not associated with the risk of mortality, CR, and AE. No RCT exists evaluating the efficacy of PE for EGPA; hence, this is required in the future. The results may affect the development of guidelines for AAV and may indicate the direction of future clinical research on AAV. TRIAL REGISTRATION UMIN R000045239 , PROSPERO CRD42020182566 .
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Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis
Walsh M, Merkel PA, Peh CA, Szpirt WM, Puechal X, Fujimoto S, Hawley CM, Khalidi N, Flossmann O, Wald R, et al
The New England journal of medicine. 2020;382(7):622-631
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Abstract
BACKGROUND More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m(2) of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).