Efficacy of Therapeutic Apheresis for Cryoglobulinemic Vasculitis Patients with Renal Involvement: A Systematic Review
Blood purification. 2023;:1-9
INTRODUCTION Therapeutic apheresis (TA) is commonly used for cryoglobulinemic vasculitis (CV) patients, but its efficacy remains uncertain. This systematic review aimed to assess the efficacy of different TA modalities, such as plasma exchange (PE), plasmapheresis (PP), and cryofiltration (CF), in treating CV patients with renal involvement. METHODS Literature search of MEDLINE, EMBASE, and Cochrane Databases was conducted up to December 2022. Studies that reported the outcomes of TA in adult CV patients with renal involvement were assessed. The protocol for this systematic review has been registered with PROSPERO (No. CRD42023417727). The quality of each study was evaluated by the investigators using the validated methodological index for non-randomized studies (minors) quality score. RESULTS 154 patients who encountered 170 episodes of serious events necessitating TA were evaluated across 76 studies. Among them, 51% were males, with a mean age ranging from 49 to 58 years. The CV types included 15 type I, 97 type II, and 13 type III, while the remaining patients exhibited mixed (n = 17) or undetermined CV types (n = 12). Among the treatment modalities, PE, PP, and CF were performed in 85 (56%), 52 (34%), and 17 patients (11%), respectively, with no identical protocol for TA treatment. The overall response rate for TA was 78%, with response rates of 84%, 77%, and 75% observed in type I, II, and III patients respectively. Most patients received steroids, immunosuppressants, and treatment targeting the underlying causative disease. The overall long-term renal outcome rate was 77%, with type I, II, and III patients experiencing response rates of 89%, 76%, and 90%, respectively. The renal outcomes in patients receiving PE, PP, and CF were comparable, with rates of 78%, 76%, and 81%, respectively. CONCLUSIONS This study presents compelling evidence that combination of TA with other treatments, especially immunosuppressive therapy, is a successful strategy for effectively managing severe renal involvement in CV patients. Among the TA modalities studied, including PE, PP, and CF, all demonstrated efficacy, with PE being the most frequently employed approach.
Comparison of multiple treatments in the management of transplant-related thrombotic microangiopathy: a network meta-analysis
Annals of hematology. 2022
Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (TA-TMA) is a fatal post-transplant complication. It has a high mortality rate and worse prognosis, but treatment strategies remain controversial. We screened 6 out of 3453 studies on the treatment of TA-TMA. These investigations compared 5 treatment strategies with a network meta-analysis approach. The final outcome was the proportion of patients who responded to these therapies. There were significant differences in response rates for each treatment. Achieving analysis through direct and indirect evidence in the rank probabilities shows that rTM (recombinant human soluble thrombomodulin) is most likely to be rank 1 (64.98%), Eculizumab intervention rank 2 (48.66%), ISM (immunosuppression manipulation) rank 3 (32.24%), TPE (therapeutic plasma exchange) intervention rank 4 (69.56%), and supportive care intervention rank 5 (70.20%). Eculizumab and ISM have significantly higher efficacy than supportive care (odds ratio (OR): 18.04, 18.21 respectively); and TPE having lower efficacy than all other TA-TMA therapies exception to supportive care. In our study, rTM and Eculizumab may be the best choice when treating TA-TMA.
Patients receiving treatment for transplantation-associated thrombotic microangiopathy (TA-TMA), (6 studies, n= 71).
Therapeutic plasma exchange (TPE).
Recombinant human soluble thrombomodulin (rTM). Eculizumab. Immunosuppression manipulation (ISM). Supportive care.
There were significant differences in response rates for each treatment. Achieving analysis through direct and indirect evidence in the rank probabilities showed that rTM was most likely to be rank 1 (64.98%), Eculizumab intervention rank 2 (48.66%), ISM rank 3 (32.24%), intervention rank 4 (69.56%), and supportive care intervention rank 5 (70.20%). Eculizumab and ISM had significantly higher efficacy than supportive care (odds ratio (OR): 18.04, 18.21 respectively); and TPE had lower efficacy than all other TA-TMA therapies exception to supportive care.
Granulomatosis With Polyangiitis Presenting With Diffuse Alveolar Hemorrhage: A Systematic Review
Granulomatosis with polyangiitis (GPA) is a systemic disease that has variable clinical expression. GPA is the most common antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Diffuse alveolar hemorrhage (DAH) is one of the least common pulmonary manifestations in patients with GPA. DAH is clinically marked by hemoptysis, anemia, and diffuse alveolar infiltrates on imaging as well as hypoxemic respiratory failure. The diagnosis and treatment are challenging. Recommendations for ANCA-associated vasculitis, in general, are already established; however, there is a knowledge gap that addresses the association of GPA and DAH. The aim of this systematic review is to focus on the main clinical aspects and treatment of patients with GPA who present with DAH. Thorough research of available literature was performed, including studies published in the last 10 years, following the Preferred Items for Systematic Review and Meta-Analysis (PRISMA) 2020 recommendations. The following databases were included: PubMed, Medline, Embase, ClinicalTrials.com, Google Scholar, and Prospero. The search terms included: [granulomatosis] AND [polyangiitis] AND [diffuse alveolar hemorrhage] OR [diffuse pulmonary hemorrhage] NOT [microscopic polyangiitis] NOT [eosinophilic granulomatosis]. NOS was used to assess the internal validity of the study in four domains, including selection, ascertainment, causality, and reporting. Our initial search identified 8989 studies. After excluding duplicated data and using our predetermined inclusion and exclusion criteria, we were able to retrieve 18 studies. Twelve out of 18 (67%) studies were case reports. Five were retrospective cohorts and one controlled trial. The average age of patients with GPA with DAH was 49.55 ± 17.54 years (18 - 76). Male individuals had a slight predominance (59%) in comparison to female individuals (41%). The hemoglobin level at the time of presentation was 8.86 mg/dL ± 1.43. The majority of patients (61.5%) reported hemoptysis. Renal involvement was present in 66.7%. Patients who required mechanical ventilation represented 61.5%. Plasmapheresis was used in 71.4%. Mortality was 20%, and gender was not associated with mortality (p = 0.822). Hemoptysis was not associated with the need for mechanical ventilation (p = 0.928). Renal impairment was not a predictor of mechanical ventilation (p = 0.207). In summary, patients with GPA and DAH were severely ill, frequently had renal impairment upon admission, and frequently required mechanical ventilation. Steroids, rituximab, and cyclophosphamide are the first-line treatment, and plasmapheresis is still in use. Eventually, extracorporeal membrane oxygenation (ECMO) can be the salvage therapy. Randomized controlled clinical trials (RCTs) are needed to address the best therapeutic options for this population.
The effects of plasma exchange in patients with ANCA-associated vasculitis: an updated systematic review and meta-analysis
BMJ (Clinical research ed.). 2022;376:e064604
OBJECTIVE To assess the effects of plasma exchange on important outcomes in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). DESIGN Systematic review and meta-analysis of randomised controlled trials. ELIGIBILITY CRITERIA Randomised controlled trials investigating effects of plasma exchange in patients with AAV or pauci-immune rapidly progressive glomerulonephritis and at least 12 months' follow-up. INFORMATION SOURCES Prior systematic reviews, updated by searching Medline, Embase, and CENTRAL to July 2020. RISK OF BIAS Reviewers independently identified studies, extracted data, and assessed the risk of bias using the Cochrane Risk of Bias tool. SYNTHESIS OF RESULTS Meta-analyses were conducted using random effects models to calculate risk ratios and 95% confidence intervals. Quality of evidence was summarised in accordance with GRADE methods. Outcomes were assessed after at least12 months of follow-up and included all-cause mortality, end stage kidney disease (ESKD), serious infections, disease relapse, serious adverse events, and quality of life. RESULTS Nine trials including 1060 participants met eligibility criteria. There were no important effects of plasma exchange on all-cause mortality (relative risk 0.90 (95% CI 0.64 to 1.27), moderate certainty). Data from seven trials including 999 participants that reported ESKD demonstrated that plasma exchange reduced the risk of ESKD at 12 months (relative risk 0.62 (0.39 to 0.98), moderate certainty) with no evidence of subgroup effects. Data from four trials including 908 participants showed that plasma exchange increased the risk of serious infections at 12 months (relative risk 1.27 (1.08 to 1.49), moderate certainty). The effects of plasma exchange on other outcomes were uncertain or considered unimportant to patients. LIMITATIONS OF EVIDENCE There is a relative sparsity of events, and treatment effect estimates are therefore imprecise. Subgroup effects at the participant level could not be evaluated. INTERPRETATION For the treatment of AAV, plasma exchange has no important effect on mortality, reduces the 12 month risk of ESKD, but increases the risk of serious infections. FUNDING No funding was received. REGISTRATION This is an update of a previously unregistered systematic review and meta-analysis published in 2014.
Patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (9 studies, n= 1,060).
No plasma exchange.
There were no important effects of plasma exchange on all-cause mortality (relative risk 0.90, moderate certainty). Data from seven trials (n= 999) reporting end stage kidney disease (ESKD) demonstrated that plasma exchange reduced the risk of ESKD at 12 months (relative risk 0.62, moderate certainty) with no evidence of subgroup effects. Data from four trials (n= 908) showed that plasma exchange increased the risk of serious infections at 12 months (relative risk 1.27, moderate certainty). The effects of plasma exchange on other outcomes were uncertain or considered unimportant to patients.
Recent Advancements in the Management of Anti-neutrophil Cytoplasmic Antibody-Associated Vasculitis: A Systematic Review
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a rare multisystem autoimmune condition that causes inflammation of small and medium-sized blood vessels and is more commonly seen in the geriatric population. ANCA-associated vasculitis (AAV) is typically characterized as necrotizing vasculitis and includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). The mortality rate remains high, with especially cardiovascular disease, infections, and malignancies being the leading causes of death. Existing treatment options depend heavily on the use of glucocorticoids (GCs), often in combination with cyclophosphamide (CYC); however, as the multitude of adverse effects associated with these agents has increased, numerous studies are being conducted to reduce not only these harmful effects but also improve remission rates. Rituximab, avacopan, corticosteroids, including intravenous pulse methylprednisolone, plasma exchange, and immunological targeting are among the emerging treatments. The purpose of this review is to emphasize the pathogenesis and traditional treatment modalities and give insights into the recent advances in managing this disorder in an attempt to spare the adverse effects of conventional therapies while achieving better remission rates with combination therapies as well. The authors explored multiple databases, employing appropriate keywords, satisfying the quality appraisal, after which a total of 14 reports were included in this review. Upon overall analysis, it can be concluded that rituximab and CYC, when used in combination, provided a safer alternative to GCs while exhibiting equal, if not superior, effectiveness and results, thus, paving the way for additional in-depth research in a larger population of interest.
Granulomatosis With Polyangiitis and Microscopic Polyangiitis: A Systematic Review and Meta-Analysis of Benefits and Harms of Common Treatments
ACR open rheumatology. 2021
OBJECTIVE The aim of this systemic review is to compare different treatments for patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) to inform evidence-based recommendations for the American College of Rheumatology (ACR)/Vasculitis Foundation (VF) Vasculitis Management Guidelines. METHODS A systemic review was conducted by searching articles in English using OVID Medline, PubMed, Embase, and the Cochrane Library. Articles were screened for suitability in addressing PICO questions, with studies presenting the highest level of evidence given preference. RESULTS A total of 729 full-text articles addressing GPA and MPA PICO questions were reviewed. For remission induction, rituximab was shown to be noninferior to cyclophosphamide (CYC) (odds ratio [OR]: 1.55, moderate certainty of evidence). The addition of plasma exchange to induction therapy in severe disease did not improve the composite end point of death or end stage renal disease (hazard ratio [HR]: 0.86 [95% confidence interval CI: 0.65, 1.13], moderate certainty of evidence). In nonsevere disease, methotrexate was noninferior to CYC for induction of remission (remission at 6 months of 90% vs. 94%). For maintenance of remission, methotrexate and azathioprine showed no difference in the risk of relapse over a mean follow-up of 29 months (HR: 0.92, [95% CI: 0.52, 1.65]low certainty of evidence). As maintenance therapy, rituximab was superior to a tapering azathioprine strategy in major relapse-free survival at 28 months (HR: 6.61, [95% CI: 1.56, 27.96], moderate certainty of evidence). In two randomized trials, longer-term azathioprine maintenance therapy (>24 months) is associated with fewer relapses without an increase in adverse events. CONCLUSION This comprehensive systematic review synthesizes and evaluates the benefits and toxicities of different treatment options for GPA and MPA.
Effects of therapeutic plasma exchange on anticoagulants in patients receiving therapeutic anticoagulation: a systematic review
Therapeutic plasma exchange (TPE) removes coagulation proteins, but its impact on therapeutic anticoagulation is unknown. We performed a systematic review of the literature to determine the coagulation effects of TPE in patients receiving systemic anticoagulation. We searched MEDLINE, CINAHL, EMBASE, and Web of Science until June 2018 for studies combining controlled vocabulary and keywords related to therapeutic plasma exchange, plasmapheresis, anticoagulants, and therapy. The primary outcome was the effect of TPE on anti-Xa activity, activated partial thromboplastin time (aPTT), or international normalized ratio (INR). The secondary outcome was reports of post-TPE bleeding or thrombosis. A total of 1830 references were screened and eight studies identified. Our selected studies (five case reports and three case series) involved 23 patients and evaluated the effects of seven anticoagulants. Six studies of unfractionated heparin, low-molecular-weight heparins, and direct oral anticoagulants demonstrated an anti-Xa level decline. Two studies of unfractionated heparin and low-molecular-weight heparins showed an aPTT increase. One study of warfarin showed a post-TPE INR increase. Reports of post-TPE bleeding occurred in two patients and thrombosis in one. In patients receiving therapeutic anticoagulation, TPE is associated with anti-Xa activity decline and aPTT and INR increase. These coagulation changes do not appear to significantly increase bleeding or thrombotic risk. Our data suggest the need for prospective studies to investigate the true clinical impact of TPE on therapeutic anticoagulation.
Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): protocol for a randomized controlled trial
BACKGROUND Granulomatosis with polyangiitis (GPA, Wegener's) and microscopic polyangiitis (MPA) are small vessel vasculitides collectively referred to as anti-neutrophil cytoplasm antibody-associated vasculitis (AAV). AAV is associated with high rates of morbidity and mortality due to uncontrolled disease and treatment toxicity. Small randomized trials suggest adjunctive plasma exchange may improve disease control, while observational evidence suggests that current oral glucocorticoid doses are associated with severe infections in patients with AAV. A randomized study of both plasma exchange and glucocorticoids is required to evaluate plasma exchange and oral glucocorticoid dosing in patients with AAV. METHODS/DESIGN PEXIVAS is a two-by-two factorial randomized trial evaluating adjunctive plasma exchange and two oral glucocorticoid regimens in severe AAV. Five hundred patients are being randomized at centers across Europe, North America, Asia, and Australasia to receive plasma exchange or no plasma exchange, and to receive standard or reduced oral glucocorticoid dosing. All patients receive immunosuppression with either cyclophosphamide or rituximab. The primary outcome is the time to the composite of all-cause mortality and end-stage renal disease.PEXIVAS is funded by the National Institute of Health Research (UK), the Food and Drug Administration (USA), the National Institutes of Health (USA), the Canadian Institute of Health Research (Canada), the National Health and Medical Research Council (Australia), and Assistance Publique (France). Additional in-kind supplies for plasma exchange are provided by industry partners (TerumoBCT, Gambro Australia, and Fresenius Australia). DISCUSSION This is the largest trial in AAV undertaken to date. PEXIVAS will inform the future standard of care for patients with severe AAV. The cooperation between investigators, funding agencies, and industry provides a model for conducting studies in rare diseases. TRIAL REGISTRATION Current Controlled Trials: (ISRCTN07757494) and clinicaltrials.gov: (NCT00987389).
Plasma exchange for induction and cyclosporine A for maintenance of remission in Wegener's granulomatosis--a clinical randomized controlled trial
Nephrology, Dialysis, Transplantation. 2011;26((1):):206-13.
BACKGROUND The use of plasma exchange (PE) for induction treatment of anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis (AAV), including Wegener's granulomatosis (WG), is still controversial. The use of PE in AAV is not commonly accepted in patients with a plasma creatinine <500 Î¼mol/L (5.7 mg/dL) despite experimental support for involvement of ANCA in the pathogenesis of vasculitis. METHODS In a single-centre study from a tertiary referral centre, 32 patients with ANCA-positive WG were treated with standard immunosuppressive therapy, prednisolone and cyclophosphamide (CYC). In addition, they were randomized to treatment with or without initial PE. After 3 months, they were further randomized in a Latin square design to continue CYC or to change to cyclosporine A (CyA) for 9 months. The renal follow-up was at least 5 years. RESULTS Renal survival after 1, 3 and 12 months, and 5 years was significantly better in the PE groups. For all groups, the kidney/patient survival was 87.5%/93.7% at 1 year and 72%/56% at 5 years. All patients who were on dialysis when recruited were dialysis dependent 5 years later. There was no difference in morbidity or mortality between PE and control groups. Multivariate analysis demonstrated that PE improved renal survival (P < 0.01) at initial plasma creatinine levels >250 µmol/L (2.85 mg/dL). Change from CYC to CyA did not influence rate of relapses or time to relapse. CONCLUSIONS PE is recommended for induction therapy in WG patients at creatinine levels >250 µmol/L (2.85 mg/dL), whereas previous randomized studies have limited PE to patients with creatinine >500 µmol/L (5.65 mg/dL).
A first-in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome
Journal of the American College of Cardiology. 2010;55((24):):2727-35.
OBJECTIVES This study aimed to determine whether serial autologous infusions of selective high-density lipoprotein (HDL) delipidated plasma are feasible and well tolerated in patients with acute coronary syndrome (ACS). BACKGROUND Low HDL is associated with increased risk of cardiovascular disease. Plasma selective delipidation converts alphaHDL to prebeta-like HDL, the most effective form of HDL for lipid removal from arterial plaques. METHODS ACS patients undergoing cardiac catheterization with >or=1 nonobstructive native coronary artery atheroma were randomized to either 7 weekly HDL selective delipidated or control plasma apheresis/reinfusions. Patients underwent intravascular ultrasound (IVUS) evaluation of the target vessel during the catheterization for ACS and up to 14 days following the final apheresis/reinfusion session. 2-D gel electrophoresis of delipidated plasmas established successful conversion of alphaHDL to prebeta-like HDL. The trial was complete with 28 patients randomized. RESULTS All reinfusion sessions were tolerated well by all patients. The levels of prebeta-like HDL and alphaHDL in the delipidated plasma converted from 5. 6% to 79. 1% and 92. 8% to 20. 9%, respectively. The IVUS data demonstrated a numeric trend toward regression in the total atheroma volume of -12. 18 +/- 36. 75 mm(3) in the delipidated group versus an increase of total atheroma volume of 2. 80 +/- 21. 25 mm(3) in the control group (p = 0. 268). CONCLUSIONS In ACS patients, serial autologous infusions of selective HDL delipidated plasma are clinically feasible and well tolerated. This therapy may offer a novel adjunct treatment for patients presenting with ACS. Further study will be needed to determine its ability to reduce clinical cardiovascular events.