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Journal of Nephrology May 2022Idiopathic membranous nephropathy is a common cause of nephrotic syndrome in adults. The Kidney Disease Improving Global Outcomes guidelines recommend rituximab or... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Idiopathic membranous nephropathy is a common cause of nephrotic syndrome in adults. The Kidney Disease Improving Global Outcomes guidelines recommend rituximab or cyclophosphamide and steroids, or calcineurin inhibitor-based therapy. However, there have been few or no head-to-head comparisons of the relative efficacy and safety of different immunosuppression regimens. We conducted a network meta-analysis to evaluate the comparative efficacy and safety of available immunosuppression strategies compared to cyclophosphamide in adults with idiopathic membranous nephropathy.
METHODS
We performed a systematic search of MEDLINE, Embase and CENTRAL for randomized controlled trials in the treatment of adults with idiopathic membranous nephropathy. The primary outcome was complete remission. Secondary outcomes were kidney failure, partial remission, estimated glomerular filtration rate, doubling of serum creatinine, proteinuria, serious adverse events, discontinuation of treatment, serious infection and bone marrow suppression.
RESULTS
Cyclophosphamide had uncertain effects on inducing complete remission when compared to rituximab (OR 0.35, CI 0.10-1.24, low certainty evidence), mycophenolate mofetil (OR 1.81, CI 0.69-4.71, low certainty), calcineurin inhibitor (OR 1.26, CI 0.61-2.63, low certainty) or steroid monotherapy (OR 2.31, CI 0.62-8.52, low certainty). Cyclophosphamide had a higher probability of inducing complete remission when compared to calcineurin inhibitor plus rituximab (OR 4.45, CI 1.04-19.10, low certainty). Compared to other immunosuppression strategies, there was limited evidence that cyclophosphamide had different effects on other pre-specified outcomes.
CONCLUSIONS
The comparative effectiveness and safety of immunosuppression strategies compared to cyclophosphamide is uncertain in adults with idiopathic membranous nephropathy.
Topics: Adult; Calcineurin Inhibitors; Cyclophosphamide; Female; Glomerulonephritis, Membranous; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Network Meta-Analysis; Rituximab; Steroids
PubMed: 35199314
DOI: 10.1007/s40620-022-01268-2 -
Clinical Transplantation Oct 2022The optimal immunosuppression protocol to prevent early acute cellular rejection (ACR) after liver transplantation (LT) avoiding prolonged hospitalization and early... (Review)
Review
BACKGROUND
The optimal immunosuppression protocol to prevent early acute cellular rejection (ACR) after liver transplantation (LT) avoiding prolonged hospitalization and early hospital readmission is undefined.
OBJECTIVES
To identify the most suitable immunosuppression regimen for inclusion in ERAS programs in order to minimize early ACR after LT and to provide expert panel recommendations DATA SOURCES: Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central.
METHODS
Systematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel. Studies from January 2000 onward focusing on early ACR were included. Rates of early renal dysfunction and infection were evaluated. CRD42021245586 RESULTS: Thirty-seven studies met inclusion criteria; 23 randomized controlled trials, 14 retrospective or prospective observational comparative or noncomparative studies. Several sources of biases which potentially confound conclusions were identified: heterogeneity in immunosuppression protocols, higher serum tacrolimus levels than currently used in clinical practice, differences in the definition of ACR.
CONCLUSIONS
Tacrolimus is the standard immunosuppression after LT and can be used in combination with other drugs such as corticosteroids and MMF, and in association with anti-IL2 receptor antibody (IL2Ra) induction. (Quality of Evidence; Low | Grade of Recommendation; Strong). Low dose or delayed introduction of tacrolimus in association with corticosteroids and MMF and/or anti-IL2Ra induction can be used to reduce acute kidney injury. (Quality of Evidence; Low | Grade of Recommendation; Strong). Use of tacrolimus in association with corticosteroids and MMF and/or anti-IL2Ra induction does not lead to increased infection rates. (Quality of Evidence; Low | Grade of Recommendation; Weak).
Topics: Humans; Mycophenolic Acid; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Retrospective Studies; Tacrolimus; Graft Rejection; Adrenal Cortex Hormones; Observational Studies as Topic
PubMed: 35143096
DOI: 10.1111/ctr.14614 -
Revue Neurologique Sep 2022Rasmussen's encephalitis (RE) is a severe, rare, chronic inflammatory brain disease resulting in drug-resistant epilepsy and progressive destruction of one hemisphere... (Review)
Review
Rasmussen's encephalitis (RE) is a severe, rare, chronic inflammatory brain disease resulting in drug-resistant epilepsy and progressive destruction of one hemisphere with loss of neurological function. RE is associated with a deterioration of background electroencephalography (EEG) activity, a progressive atrophy on magnetic resonance imaging (MRI) imaging and an extensive positron emission tomography hypometabolism over the affected hemisphere. RE is an immune-mediated disease, with a predominant role of CD8+ T cytotoxic cells, microglial cells, and activation of inflammasome pathway. The diagnosis of RE is based on clinical (intractable epilepsy and neurological deterioration), electrophysiological (unilateral EEG slowing) and MRI (hemiatrophy) criteria. Antiseizure medications are generally unable to stop seizures. The most effective procedure is hemispherotomy (surgical disconnection of one cerebral hemisphere), but this is associated with permanent motor and neurological deficits. Treatments targeting the immune system are recommended especially in the early stages of the disease or in patients with slow disease progression and mild deficits and/or not eligible for surgery. Based on the pathophysiology, several immunotherapies have been tried in RE (none exhaustively: corticosteroid, intravenous immunoglobulins, tacrolimus, azathioprine, adalimumab, mycophenolate mofetil, natalizumab). However, only small cohorts have been reported without comparative study. In this review, we will summarise some pathophysiological mechanisms of RE, before reporting the literature data concerning immunotherapies. We then discuss the limitations of these studies and the prospects for further research.
Topics: Atrophy; Brain; Drug Resistant Epilepsy; Electroencephalography; Encephalitis; Humans; Magnetic Resonance Imaging
PubMed: 35131107
DOI: 10.1016/j.neurol.2022.01.007 -
Annals of Transplantation Dec 2021BACKGROUND Tacrolimus is an established component of immunosuppressive regimens for kidney transplant recipients (KTRs); however, data comparing long-term outcomes... (Meta-Analysis)
Meta-Analysis
Efficacy and Safety of Tacrolimus-Based Maintenance Regimens in De Novo Kidney Transplant Recipients: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.
BACKGROUND Tacrolimus is an established component of immunosuppressive regimens for kidney transplant recipients (KTRs); however, data comparing long-term outcomes between formulations are lacking. We conducted a systematic literature review and network meta-analysis assessing tacrolimus (primarily Advagraf [once-daily] and Prograf [twice-daily])-based maintenance regimens. MATERIAL AND METHODS Embase, MEDLINE, and Cochrane databases and congress proceedings were searched to identify studies of adult de novo KTRs who received tacrolimus-based therapy in phase II/III randomized controlled trials. Outcomes were acute rejection, graft/patient survival, and incidence of new-onset diabetes mellitus after transplantation (NODAT) and cytomegalovirus (CMV) infection. Bayesian network meta-analysis was used to analyze treatment effects on graft/patient survival. RESULTS Sixty-eight publications (61 primary) were included. Of 21 publications reporting graft rejection following Advagraf or Prograf treatment in ≥1 study arm, 12-month biopsy-proven acute rejection (BPAR) ranged from 3.3% with Prograf to 55.0% with mycophenolic acid (MPA)+corticosteroids (CS); >24 month BPAR ranged from 0% to 58.7% (the latter with bleselumab-based therapy). Fourteen publications reported graft loss following Advagraf (0-9.6%) or Prograf (0-7.5%). Patient mortality ≤24 months after transplantation (14 publications) ranged from 0% to 8.1% with Advagraf or Prograf. Advagraf+MPA+CS and reference treatment, Prograf+MPA+CS, were associated with a similar risk of graft loss (odds ratio 1.19; 95% credible-interval 0.51, 3.06) and mortality (odds ratio 1.21; 95% credible-interval 0.1557, 9.03). Incidence of NODAT and CMV varied by treatment arm. CONCLUSIONS Graft loss and patient mortality rates were generally comparable between Advagraf- and Prograf-based regimens. Further prospective studies are needed to evaluate longer-term outcomes.
Topics: Adult; Bayes Theorem; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Network Meta-Analysis; Randomized Controlled Trials as Topic; Tacrolimus
PubMed: 34963678
DOI: 10.12659/AOT.933588 -
Journal of Neuroimmunology Feb 2022Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system, which mainly involves the optic nerve and spinal cord. Frequent... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system, which mainly involves the optic nerve and spinal cord. Frequent relapse can accumulate the degree of disability. At present, the main treatment options are immunosuppressants and blood purification. The first-line immunosuppressants for NMOSD are mainly rituximab (RTX), mycophenolate mofetil (MMF) and azathioprine (AZA). Therefore, we designed this systematic review and meta-analysis to evaluate the safety and effect of the above three drugs in the treatment of NMOSD patients.
METHODS
The following Medical Subject Heading (MeSH) and related entry terms are used to search English literature in PubMed, MEDLINE and CENTRAL databases, respectively. MeSH include: Neuromyelitis optic and Rituximab or Azathioprine or Mycophenolate Mofetil; entry terms include: NMO Spectrum Disorder, NMO Spectrum Disorders, Neuromyelitis Optica (NMO) Spectrum Disorder, Neuromyelitis Optica Spectrum Disorders, Devic Neuromyelitis Optica, Neuromyelitis Optica, Devic, Devic's Disease, Devic Syndrome, Devic's Neuromyelitis Optica, Neuromyelitis Optica (NMO) Spectrum Disorders, CD20 Antibody, Rituximab CD20 Antibody, Mabthera, IDEC-C2B8 Antibody, GP2013, Rituxan, Mycophenolate Mofetil, Mofetil, Mycophenolate, Mycophenolic Acid, Morpholinoethyl Ester, Cellcept, Mycophenolate Sodium, Myfortic, Mycophenolate Mofetil Hydrochloride, Mofetil Hydrochloride, Mycophenolate, RS 61443, RS-61443, RS61443, azathioprine sodium, azathioprine sulfate (note: literature retrieval operators "AND" "OR" "NOT" are used to link MeSH with Entry Terms.) The literature search found a total of 3058 articles about rituximab, mycophenolate mofetil and azathioprine in the treatment of NMOSD, 63 of which were included in this study after a series of screening.
RESULTS
930,933,732 patients with NMOSD were enrolled, who had been treated with MMF, AZA and RTX, respectively. The pooled standardized mean difference (SMD) of EDSS before and after RTX treated was -0.58 (95%CI: -0.72, -0.44) (I = 0%, p = 0.477), before and after MMF treated was -0.47 (95%CI: -0.73, -0.21) (I = 85.6%, p<0.001), before and after AZA treated was -0.41 (95%CI: -0.60, -0.23) (I = 65.4%, p<0.001). there was no significant difference in the effect of the three drugs on reducing EDSS scores (RTX vs MMF, p = 0.522; RTX vs AZA, p = 0.214; MMF vs AZA, p = 0.732). The pooled standardized mean difference (SMD) of ARR before and after RTX treated was -1.45 (95%CI: -1.72, -1.18) (I = 72.4%, p<0.001), before and after MMF treated was -1.14 (95%CI: -1.31, -0.97) (I = 54.5%, p<0.001), before and after AZA treated was -1.11 (95%CI: -1.39, -0.83) (I = 83.4%, p<0.001). RTX significantly reduced ARR compared with the other two drugs (RTX vs MMF, p = 0.039; RTX vs AZA, p = 0.049; MMF vs AZA, p = 0.436).
CONCLUSION
The results of this systematic review and meta-analysis showed that the treatment of NMOSD patients with RTX, MMF and AZA is associated with decreased number of relapses and disability improvement as well, and there was no significant difference in the effect of the three drugs on reducing EDSS scores, but RTX significantly reduced ARR compared with the other two drugs.
Topics: Azathioprine; Humans; Immunosuppressive Agents; Immunotherapy; Mycophenolic Acid; Neuromyelitis Optica; Rituximab
PubMed: 34959021
DOI: 10.1016/j.jneuroim.2021.577790 -
Therapeutic Advances in Neurological... 2021The adverse events (AEs) of rituximab (RTX) for neuromyelitis optica spectrum disorder (NMOSD) are incompletely understood.
BACKGROUND
The adverse events (AEs) of rituximab (RTX) for neuromyelitis optica spectrum disorder (NMOSD) are incompletely understood.
AIM
To collate information on the reported the AEs of RTX in NMOSD and assess the quality of evidence.
METHODS
PubMed, EMBASE, Web of Science, Cochrane Library, Wanfang Data, CBM, CNKI, VIP, clinicaltrials.gov, and so on were searched for studies with control groups as well as for case series that had assessed the RTX-associated AEs. The incidence of AEs and the comparison of AE risks among different therapies were pooled. The GRADE was developed for evidence quality.
RESULTS
A total of 3566 records were identified. Finally, 36 studies (4 RCTs, 6 crochet studies, 2 NRCTs, and 24 case series), including 1542 patients (1299 females and 139 males), were included for final analyses. Rates of patients with any AEs, any serious AEs (SAEs), infusion-related AEs, any infection, respiratory infection, urinary infection, and death were 28.57%, 5.66%, 27.01%, 17.36%, 4.76%, 4.76%, and 0.17%, respectively. The results from subgroup analysis showed that AE rates were most likely not associated with covariates such as duration of illness and study designs. Very low-quality evidence suggested that the risk ratios (RR) of any AEs (0.84, 95% CI = 00.42-1.69, = 0.62) and any infections (1.24 95% CI = 0.18-8.61) of RTX were similar to that of azathioprine, and the RR of any AEs of RXT was akin to that of mycophenolate mofetil (0.66, 95% CI = 0.32-1.35 = 0.26). Evidence of low to high quality showed the lower RR of RTX in other AEs, but not in infusion-related AEs. Strategies to handle AEs focused on symptomatic treatments.
CONCLUSIONS
RTX is mostly safer than other immunosuppressants in NMOSD: the incidence of RTX-associated AEs was not high, and when present, the AEs were usually mild or moderate and could be well controlled. Given its efficacy and safety, RTX could be recommended as a first-line treatment for NMOSD.
PubMed: 34950240
DOI: 10.1177/17562864211056710 -
Nephrology, Dialysis, Transplantation :... Oct 2022Uncertainties exist about the use of mycophenolate mofetil (MMF) in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV), particularly for remission... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Uncertainties exist about the use of mycophenolate mofetil (MMF) in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV), particularly for remission maintenance.
METHODS
Systematic review and meta-analysis of phase II and III trials assessing the use of MMF in AAV, granulomatosis with polyangiitis and microscopic polyangiitis (MPA). A comprehensive search of several databases (Medline, EMBASE, Cochrane, Web of Science, Scopus) from inception to 5 May 2020 has been conducted. Trial data were extracted to estimate odds ratios (ORs) and estimates (ES) for MMF efficacy (remission-induction and maintenance). Severe adverse effects (SAEs) were collected.
RESULTS
From 565 articles captured, 10 met the predefined criteria, 5 phase II and 5 III trials; 4 assessed remission-induction, 3 remission maintenance and 3 both. The pooled OR for remission-induction at 6 months was 1.06 (95% confidence interval 0.74, 1.52), with no significant difference by subgroup meta-analysis of trials stratified by different study-level features (i.e. kidney disease, MPA, myeloperoxidase-ANCA positivity, newly diagnosed disease) (P > 0.05). The overall ES for remission maintenance at the end of follow-up ranged between 51% and 91% (I2 = 74.8%). Subgroup meta-analysis identified kidney involvement as a possible source of heterogeneity, yielding a significantly higher rate of sustained remission in trials enrolling only patients with kidney involvement (92%, 76-100%) versus those enrolling patients with and without kidney involvement (56%, 45-66%). Results were similar in multiple sensitivity analyses. During follow-up, the frequency of SAEs in MMF-based treatment arms was 31.8%.
CONCLUSIONS
In AAV, MMF use was significantly associated with higher sustained remission rates in trials enrolling only patients with kidney involvement. These findings might influence clinical practice.
Topics: Humans; Mycophenolic Acid; Antibodies, Antineutrophil Cytoplasmic; Peroxidase; Immunosuppressive Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Microscopic Polyangiitis; Remission Induction
PubMed: 34910216
DOI: 10.1093/ndt/gfab357 -
American Journal of Transplantation :... Mar 2022The effectiveness of T cell-mediated rejection (TCMR) therapy for achieving histological remission remains undefined in patients on modern immunosuppression. We... (Meta-Analysis)
Meta-Analysis
The effectiveness of T cell-mediated rejection (TCMR) therapy for achieving histological remission remains undefined in patients on modern immunosuppression. We systematically identified, critically appraised, and summarized the incidence and histological outcomes after TCMR treatment in patients on tacrolimus (Tac) and mycophenolic acid (MPA). English-language publications were searched in MEDLINE (Ovid), Embase (Ovid), Cochrane Central (Ovid), CINAHL (EBSCO), and Clinicaltrials.gov (NLM) up to January 2021. Study quality was assessed with the National Institutes of Health Study Quality Tool. We pooled results using an inverse variance, random-effects model and report the binomial proportions with associated 95% confidence intervals (95% CI). Statistical heterogeneity was explored using the I statistic. From 2875 screened citations, we included 12 studies (1255 participants). Fifty-eight percent were good/high quality while the rest were moderate quality. Thirty-nine percent of patients (95% CI 0.26-0.53, I 77%) had persistent ≥Banff Borderline TCMR 2-9 months after anti-rejection therapy. Pulse steroids and augmented maintenance immunosuppression were mainstays of therapy, but considerable practice heterogeneity was present. A high proportion of biopsy-proven rejection exists after treatment emphasizing the importance of histology to characterize remission. Anti-rejection therapy is foundational to transplant management but well-designed clinical trials in patients on Tac/MPA immunosuppression are lacking to define the optimal therapeutic approach.
Topics: Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; T-Lymphocytes; Tacrolimus
PubMed: 34860468
DOI: 10.1111/ajt.16907 -
Frontiers in Medicine 2021The probable impact of a maintenance immunosuppressant (IS) on liver transplant (LT) recipients with coronavirus disease 2019 (COVID-19) remains unexplored. Our...
The probable impact of a maintenance immunosuppressant (IS) on liver transplant (LT) recipients with coronavirus disease 2019 (COVID-19) remains unexplored. Our specific aim was to approximate the prognosis of LT recipients with COVID-19 on the standard maintenance IS. We searched separate databases for the qualified studies in between December 2019 and June 25, 2021. Ultimately, a meta-analysis was carried out using a fixed-effect or random-effect model based on the heterogeneity. In a total of eight studies and 509 LT recipients with COVID-19, the pooled rates of severity and mortality during all the combined immunosuppressive therapies were 22.4 and 19.5%, respectively. Our study sufficiently showed that an immunosuppressive therapy in LT recipients with COVID-19 was significantly associated with a non-severe COVID-19 [odds ratio (OR): 11.49, 95% CI: 4.17-31.65; < 0.001] and the survival of the patients (OR: 17.64, 95% CI: 12.85-24.22; < 0.001). Moreover, mammalian target of rapamycin inhibitor (mTORi) typically had the lowest rate of severity and mortality compared to other ISs such as calcineurin inhibitors (CNIs), steroids, and antimetabolites, i.e., severity (13.5 vs. 21.1, 24.7, and 26.3%) and mortality (8.3 vs. 15, 17.2, and 12.1%), respectively. Contrary to the general opinions, our meta-analysis showed comorbidities such as diabetes, hypertension, cardiopulmonary disorders, chronic kidney disease (CKD), age >60, the duration of LT to the diagnosis of COVID-19, primary disease for LT, and obesity were not significantly associated with the severity and mortality in LT recipients with COVID-19 under an immunosuppressive therapy. However, our pooled analysis found that LT recipients with COVID-19 and without comorbidities have a less severe disease and low mortality rate compared to those with both COVID-19 and comorbidities. In conclusion, LT recipients with COVID-19 undergoing immunosuppressive therapies are not significantly associated with the severity and mortality. Therefore, taking the risk of organ rejection into a key consideration, a complete withdrawal of the IS may not be wise. However, mycophenolate mofetil (MMF) might be discontinued or replaced from an immunosuppressive regimen with the CNIs- or mTORis-based immunosuppressive therapy in some selected LT recipients with COVID-19, depending upon the severity of the disease.
PubMed: 34859012
DOI: 10.3389/fmed.2021.756922 -
Therapeutic Advances in Neurological... 2021A considerable number of patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) will experience a relapse, but the effect of maintenance...
BACKGROUND
A considerable number of patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) will experience a relapse, but the effect of maintenance therapies on re-attack rates is currently unknown.
OBJECTIVE
To investigate the efficacy and safety of immunosuppressive therapy for preventing disease relapses in patients with MOGAD, including rituximab (RTX), mycophenolate mofetil (MMF), and azathioprine (AZA).
METHODS
English-language studies published prior to August 31, 2020, were searched in the NCBI (PubMed), ISI Web of Science, and the Cochrane Library databases. Patient characteristics, treatment regimens, outcome measures, and adverse effects were retrieved.
RESULTS
We enrolled 11 studies in the final meta-analysis, including 346 patients with MOGAD. RTX therapy was demonstrated to result in reduced mean annualized relapse rate (ARR) by 1.35 (95% confidence interval (CI): 0.85-1.85) and reduced mean Expanded Disability Status Scale score by 0.80 (95% CI: 0.53-1.08) in patients with MOGAD. MMF therapy was associated with the mean ARR decreasing by 0.83 (95% CI: 0.31-1.35), and AZA was related to the mean ARR decreasing by 1.71 (95% CI: 0.83-2.58). The reported discontinuation rates of RTX, MMF, and AZA therapy due to adverse effects were 3/197 (1.52%), 3/39 (7.69%), and 4/37 (10.81%), respectively.
CONCLUSION
The study provided evidence to support the efficacy of RTX, MMF, and AZA on the preventive treatment in patients with MOGAD. However, large randomized controlled trials are still needed in the future.
PubMed: 34790259
DOI: 10.1177/17562864211054157