Autologous Cultured Bone Marrow-Derived Mesenchymal Stem Cells in a Fibrin Spray to Treat Venous Ulcers: A Randomized Controlled Double-Blind Pilot Study
Surgical technology international. 2022;40
We treated a small cohort of venous ulcers that were very unresponsive to standard and advanced therapies with autologous cultured bone marrow-derived mesenchymal stem cells (MSCs). This pilot clinical trial was randomized, controlled, and double-blinded. Subjects were treated with either normal saline (Group A), fibrin spray alone (Group B), or MSCs in fibrin (1 million cells/cm2 of wound bed surface) (Group C). The control and test materials were applied to the wound using a double-barreled syringe with thrombin and fibrinogen (with or without MSCs) in each barrel, or saline alone in both barrels. The MSCs were separated, cultured in vitro, and expanded in a dedicated Good Manufacturing Practice (GMP) facility from 30-50 ml of bone marrow aspirate obtained from the iliac crest in Group C subjects. To ensure that the study remained controlled and blinded, subjects who were randomized to one of the two control arms (saline or fibrin) underwent sham bone marrow aspiration performed by a hematologist who anesthetized the iliac crest area down to and pushing against the periosteum, but without penetrating the bone marrow. Therefore, both the clinician who evaluated wound progress and the study subjects had no knowledge of whether bone aspiration was actually performed and what treatment had been applied to the wound. The study was performed after full FDA investigational new drug (IND) approval. The primary endpoint was the rate of healing (wound closure as linear healing from the wound margins in cm/week), as measured by the Gilman equation. One-way ANOVA was used to calculate the statistical significance of differences between the mean healing rates of each of the 3 treatment groups every 4 weeks and over the 24 weeks of treatment. Overall, treatment with MSCs accelerated the healing rate by about 10-fold compared to those in the saline and fibrin control groups. Although the total number of patients in this pilot study was small (n=11), the statistical significance was surprisingly promising: p<0.01 and f-ratio of 15.9358. No serious adverse events were noted. This small but carefully performed prospective, controlled, randomized, and double-blinded pilot study in a rare population of totally unresponsive patients adds to previous reports showing the promise of MSCs in the treatment of chronic wounds and provides proof of principle for how to approach this type of very demanding clinical and translational research.
A systematic review and meta-analysis of randomized controlled trials evaluating pharmacologic therapies for acute and recurrent pericarditis
Trends in cardiovascular medicine. 2022
Acute idiopathic pericarditis (AIP) is a benign inflammatory condition associated with high recurrence rates. Non-steroidal anti-inflammatory drug (NSAIDs) and colchicine are the recommended therapies. Our objective was to systematically assess effects of pharmacological therapies on recurrences or treatment failure in patients with first and subsequent AIP episodes. PubMed, BioMedCentral, Cochrane, Clinicaltrials.gov, Google Scholar and EMBASE (Ovid) were searched up to April 2020 for randomized controlled trials (RCT) evaluating NSAIDs, indomethacin, colchicine, steroids, intravenous immunoglobulins, immunomodulators, or interleukin receptor antagonists in adult patients with acute episode of idiopathic pericarditis. Mantel-Haenzel random effects models were used for meta-analyses, and effects were reported as odds ratios (ORs) and their 95% confidence intervals (CI). Six RCTs of colchicine plus NSAIDs (n=914 patients) and one RCT of anakinra (n=21) were found. No RCTs testing NSAIDs or corticosteroids were identified. Colchicine plus NSAIDs and anakinra significantly reduced recurrence (OR 0.37; 95%CI 0.27-0.51; and OR 0.02; 95%CI, 0.00-0.32, respectively). Colchicine plus NSAIDs also reduced treatment failure (OR 0.29; 95%CI 0.21-0.41). No differences in adverse events between colchicine and placebo were found (OR 1.16; 95%CI 0.72 to 1.86). In conclusion, Colchicine plus NSAIDS and anakinra are efficacious for preventing AIP recurrences. Colchicine reduces treatment failure as well. Although its use is supported by clinical experience, no solid evidence is currently available for the role of NSAIDs or steroids in the treatment of AIP.
Efficacy and safety of intravenous immunoglobulin for treating refractory livedoid vasculopathy: a systematic review
Therapeutic advances in chronic disease. 2022;13:20406223221097331
INTRODUCTION Intravenous immunoglobulin (IVIG) was reported to be the third most used monotherapy in livedoid vasculopathy (LV). There is currently a lack of randomized controlled clinical trials and no standardized therapeutic regimen for IVIG therapy in LV. METHODS We performed a systematic review of the efficacy and safety of IVIG in treating patients with LV using PubMed, Cochrane, and Embase databases. RESULTS Eighty LV patients from 17 articles were included, receiving IVIG therapy at a dose of 1-2.1 g/kg body weight every 4 weeks. The effective rate of IVIG therapy in LV patients was 95% (76/80) in published studies, showing a good clinical response for resolution of pain, skin ulcerations, and neurological symptoms, and reducing the dependence on glucocorticoids and immunosuppressive agents. IVIG therapy was well tolerated, and no severe adverse events were observed. CONCLUSION Overall, to a certain degree, IVIG is probably a safe and effective treatment alternative for refractory LV patients, which still need to be confirmed by large-scale randomized controlled clinical trials.
Intravenous immunoglobulin for chronic residual peripheral neuropathy in microscopic polyangiitis: A multicentre randomised double-blind trial
Modern rheumatology. 2022
OBJECTIVES We conducted a Phase 3, multicentre randomised, double-blind, placebo-controlled, parallel-group trial to evaluate efficacy and safety of intravenous immunoglobulin (IVIg) in patients with glucocorticoid-refractory neuropathy associated with microscopic polyangiitis. METHODS Patients received immunoglobulin or placebo intravenously for five consecutive days at baseline and after four weeks. IVIg and placebo groups received placebo and IVIg, respectively, after eight weeks. The primary and major secondary endpoint were least squares mean (LS mean) of change in manual muscle test (MMT) sum score after eight and four weeks, respectively. RESULTS A total of 37 patients were randomised into two groups (IVIg 19, placebo 18). The LS mean for change in MMT sum score after eight weeks was 9.02 for IVIg and 6.71 for placebo (difference 2.32, 95% CI -2.60 to 7.23, p = .345) and after four weeks was 6.81 and 2.83 (difference 3.99, 95% CI -1.22 to 9.19, p = .129). There were no new safety concerns for IVIg. CONCLUSIONS MMT sum scores improved with IVIg compared with placebo after eight weeks of dosing and two courses of treatment, but the differences were not statistically significant, and the results showed no clear efficacy of IVIg in this patient population. No new safety concerns were raised.
Intravenous Immunoglobulin Therapy in Adult Patients with Chronic Idiopathic Cardiomyopathy and Cardiac Parvovirus B19 persistence
European journal of heart failure. 2020
AIM: Previous uncontrolled studies indicated a possible benefit of intravenous immunoglobulin (IVIg) in parvovirus B19 (B19V)-related dilated cardiomyopathy (DCM). This randomized, double-blind, placebo-controlled single-centre trial investigated the benefits of IVIg beyond conventional therapy in idiopathic chronic DCM patients with B19V persistence (NCT00892112). METHODS AND RESULTS Fifty patients (39 men; mean(±SD) age 54±11years) with chronic (>6 months) idiopathic DCM on optimal medical therapy, left ventricular ejection fraction (LVEF) <45%, and endomyocardial biopsy (EMB) B19V load of >200copies/μgDNA were blindly randomized to either IVIg (n=26, 2g/kg over four days) or placebo (n=24). The primary outcome was change in LVEF at six months after randomization. Secondary outcomes were change in functional capacity assessed by 6-minute walking test (6mwt), quality of life (Minnesota Living with Heart Failure Questionnaire (MLHFQ), left ventricular end-diastolic volume (LVEDV), and EMB B19V load at six months after randomization. LVEF significantly improved in both IVIg and placebo group (absolute mean (±SD) increase 5±9%, P=0.011 and 6±10%, P=0.008, respectively), without a significant difference between both groups (P=0.609). Additionally, change in 6mwt (median [IQR] IVIg 36[13;82] vs placebo 32[5;80]m, P=0.573), MLHFQ (IVIg 0[-7;5] vs placebo -2[-6;6], P=0.904) and LVEDV (IVIg -16±49 vs placebo -29±40ml/m(2) , P=0.334) did not significantly differ between both groups. Moreover, despite increased circulating B19V antibodies upon IVIg administration, reduction in cardiac B19V did not significantly differ between groups. CONCLUSION IVIg therapy does not significantly improve cardiac systolic function or functional capacity beyond standard medical therapy in patients with idiopathic chronic DCM and cardiac B19V persistence.
Intravenous immunoglobulin for presumed viral myocarditis in children and adults
The Cochrane database of systematic reviews. 2020;8:Cd004370
BACKGROUND This is an update of a previous review. Case reports and case series have described dramatic responses to intravenous immunoglobulin (IVIG) in people with presumed viral myocarditis, and its administration has become commonplace. OBJECTIVES The primary objective of this review was to compare event-free (death, requirement for a cardiac transplant, or placement of a left ventricular assist device) or overall (death) survival of adults and children with presumed viral myocarditis treated with IVIG versus those who did not receive IVIG. A secondary objective was to determine if a group of patients with presumed viral myocarditis could be identified (on the basis of age, duration of symptoms, acuity of onset of symptoms, cardiac function at presentation, virological results, or the presence or absence of histological evidence of acute myocarditis on cardiac biopsy in patients in whom a biopsy was performed) who would be the most likely to benefit from IVIG. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, DARE, CINAHL, Web of Science Core Collection, and LILACS in July 2019, and two trial registries in November 2019. We contacted authors of trials and checked reference lists of relevant papers. We applied no language restrictions. SELECTION CRITERIA We included studies if (1) participants had a clinical diagnosis of acute myocarditis with a left ventricular ejection fraction (LVEF) ≤ 0.45, left ventricular end-diastolic diameter (LVEDD) > 2 standard deviations (SDs) above the norm, or a left ventricular shortening fraction (LVSF) > 2 SDs below the mean, with duration of cardiac symptoms < 6 months; (2) participants had no evidence of non-infectious or bacterial cardiac disease; and (3) participants were randomly assigned to receive at least 1 g/kg of IVIG versus no IVIG or placebo. We excluded studies if (1) participants had received immunosuppression before outcome assessment; or (2) onset of myocarditis was reported to have occurred < 6 months postpartum. DATA COLLECTION AND ANALYSIS Two review authors independently screened the search results and extracted data. We assessed risk of bias with the Cochrane 'Risk of bias' tool. We conducted meta-analysis for two outcomes (overall survival and improvement in LVEF) with two adult trials. Other meta-analyses were not possible because only three relevant trials were included, and researchers analysed markedly different populations and used different outcome measures. MAIN RESULTS In this update we added two trials to the two previously included trials. A quasi-randomised trial was previously included due to a paucity of evidence from randomised trials; however, with the addition of two new randomised trials, it was removed from this update. For two adult trials, the overall risk of bias was unclear with very low-certainty evidence for all outcomes. The first trial studied 62 adults with recent-onset dilated cardiomyopathy randomly assigned to receive IVIG or an equivalent volume of 0.1% albumin in a blinded fashion. The effect on event-free survival between groups was uncertain (risk ratio (RR) of any event 1.76, 95% confidence interval (CI) 0.48 to 6.40). The second trial studied 41 adults with acute myocarditis randomised to either high-dose IVIG (1 to 2 g/kg over two days) or no treatment. The IVIG group reported greater survival time after 60 days (no raw data, P < 0.01), but the evidence is uncertain. We pooled the reported number of deaths in both trials, with no evidence of a difference between groups (RR 0.91, 95% CI 0.23 to 3.62, I(2) = 31%, very low-certainty evidence). The evidence on the effect of IVIG treatment on LVEF (pooled mean difference (MD) -0.01, 95% CI -0.06 to 0.05) after 12 months and an unknown time frame is uncertain. The results for functional capacity, assessed by peak oxygen consumption at 12 months, were uncertain (MD -0.80, 95% CI -4.57 to 2.97). The results for infusion-related side effects were also uncertain due to a very large CI (RR 20.29, 95% CI 1.25 to 329.93). Lastly, there was uncertain evidence addressing failure to attain complete recovery (RR 0.46, 95% CI 0.19 to 1.14). Evidence for improvement in LVEDD, left ventricular shortening fraction, and hospitalisation status in adults was not reported. In the single included paediatric trial, the overall risk of bias was low with very low-certainty evidence for all outcomes. The trial included 86 children in Egypt presenting with acute myocarditis. Children were randomly assigned to 1 g/kg IVIG daily for two consecutive days or placebo followed by echocardiography one and six months post randomisation for recording of LVEDD and LVSF. The evidence for overall survival after six months was uncertain (risk of death RR 0.48, 95% CI 0.20 to 1.15). The evidence was also uncertain for improvement in LVEDD and LVSF after six months (LVEDD MD -4.00, 95% CI -9.52 to 1.52; LVSF no raw data). Evidence for improvement in LVEF, functional capacity, side effects, complete recovery, and hospitalisation status in children was not reported. AUTHORS' CONCLUSIONS Evidence from two trials of very low certainty and with unclear risk of bias provides contradictory evidence on the use of IVIG in the treatment of adults with presumed viral myocarditis. One trial reported that use of IVIG results in longer survival time after 60 days, whilst the other trial found that IVIG does not provide an appreciable benefit. The evidence of a difference in event-free or overall survival, LVEDD, or LVSF is of very low certainty in a single paediatric trial with a low risk of bias. Until higher-quality studies with low risk of bias and larger sample sizes have demonstrated benefit in a particular group of patients, the evidence for treatment with IVIG for presumed viral myocarditis is uncertain. Further studies of the pathophysiology of myocarditis would lead to improved diagnostic criteria, which would facilitate future research.
Corticosteroids and Intravenous Immunoglobulin in Pediatric Myocarditis: A Meta-Analysis
Frontiers in pediatrics. 2019;7:342
Background: The efficacy of corticosteroids and intravenous immunoglobulin (IVIG) in pediatric myocarditis remains controversial. Objectives: The authors performed a meta-analysis to assess the therapeutic efficacy of corticosteroids and IVIG in children with myocarditis. Methods: We retrieved the trials on corticosteroids and IVIG therapy, respectively, in pediatric myocarditis from nine databases up to December 2018. Statistical analysis was performed using Review Manager 5.3. Results: Our analysis included 8 studies and 334 pediatric patients. The data demonstrated that children receiving corticosteroids showed no significant improvement on left ventricular ejection fraction (LVEF) from 1 to 8 month-follow-up (MD = 5.17%, 95% CI = -0.26% to 10.60%, P = 0.06), and no significant improvement in death or heart transplantation incidence at the end of follow-up (OR = 1.33, 95% CI = 0.27-6.70, P = 0.73). However, children receiving IVIG revealed a statistically remarkable increase in LVEF at a follow-up over the course of 6 months to 1 year (MD = 18.91%, 95% CI = 11.74-26.08%, P < 0.00001), and a decrease in death or heart transplantation at the end of follow-up (OR = 0.31, 95% CI = 0.12-0.75, P = 0.01). Further comparisons showed that the mortality and heart transplantation rate of children with myocarditis treated with IVIG were significantly lower than those with corticosteroid therapy (t' = 11.336, P < 0.001). Conclusions: IVIG might be beneficial to improve LVEF and survival for myocarditis in children. However, the present evidence does not support corticosteroids as superior to conventional therapy in children with myocarditis. Further randomized controlled trials with a larger sample size are required.
Role of intravenous immunoglobulin therapy in the survival rate of pediatric patients with acute myocarditis: A systematic review and meta-analysis
Scientific reports. 2019;9(1):10459
The treatment of pediatric myocarditis is controversial, and the benefits of intravenous immunoglobulin (IVIG) are inconclusive due to limited data. We searched studies from PubMed, MEDLINE, Embase, and Cochrane Library databases since establishment until October 1st, 2018. Thirteen studies met the inclusion criteria. We included a total of 812 patients with IVIG treatment and 592 patients without IVIG treatment. The meta-analysis showed that the survival rate in the IVIG group was higher than that in the non-IVIG group (odds ratio = 2.133, 95% confidence interval (CI): 1.32-3.43, p = 0.002). There was moderate statistical heterogeneity among the included studies (I(2) = 35%, p = 0.102). However, after adjustment using Duval and Tweedie's trim and fill method, the point estimate of the overall effect size was 1.40 (95% CI 0.83, 2.35), which became insignificant. Moreover, the meta-regression revealed that age (coefficient = -0.191, 95% CI (-0.398, 0.015), p = 0.069) and gender (coefficient = 0.347, 95% CI (-7.586, 8.279), p = 0.93) were not significantly related to the survival rate. This meta-analysis showed that IVIG treatment was not associated with better survival. The use of IVIG therapy in acute myocarditis in children cannot be routinely recommended based on current evidence. Further prospective and randomized controlled studies are needed to elucidate the effects of IVIG treatment.
Efficacy and safety of prothrombin complex concentrate for vitamin K antagonist-associated intracranial hemorrhage: a systematic review and meta-analysis
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2019
BACKGROUND Prothrombin complex concentrate (PCC) is the treatment of choice in vitamin K antagonist-associated intracranial hemorrhage (VKA-ICH). However, the efficiency and safety associated with their use remain unclear. AIMS This study aimed to assess the current evidence of the clinical outcomes in patients with VKA-ICH treated with or without PCC. A meta-analysis was conducted. Two randomized controlled trials and 19 observational studies were included. PCC use demonstrated a significant increased likelihood of international normalized ratio (INR) normalization (OR = 3.76; 95% CI 1.74-8.12), shortened time to INR correction (MD = - 1.30; 95% CI - 2.08 to - 0.53) and reduction of hematoma expansion (HE) rate (OR = 0.37; 95% CI 0.23-0.60). Although PCC use revealed a statistical reduction at 30-day mortality (OR = 0.62; 95% CI 0.50-0.78), the result was inconsistent with mortality at discharge (OR = 1.03; 95% CI 0.68-1.57) and 90-day follow-up (OR = 0.50; 95% CI 0.24-1.07), both of which yielded no significant difference. When subgroup analyses were performed focus on PCC only treatment with FFP, no statistically significant difference was observed in 30-day mortality (OR = 0.43; 95% CI 0.11-1.71) as well. Besides, significant difference was not found in neurologic improvement at discharge (OR = 1.85; 95% CI 0.32-10.75), 30-day follow-up (OR = 3.00; 95% CI 0.93-9.70), or 90-day follow-up (OR = 1.55; 95% CI 0.84-2.86). No statistically significant difference was noted in the risk of thromboembolism following PCC administration (OR = 0.61; 95% CI 0.23-1.63). CONCLUSIONS PCC use for VKA-ICH reversal was associated with a significant reduction in INR and HE rate, without an increased risk of thromboembolic events. However, this reduction was not associated with improvement in neurologic deficits or overall survival. Well-designed randomized trials with special considerations to the aspect are necessary.
The therapeutic efficacy of intravenous immunoglobulin in anti-neutrophilic cytoplasmic antibody-associated vasculitis: a meta-analysis
Rheumatology (Oxford, England). 2019
OBJECTIVES The therapeutic effects of IVIG in patients with ANCA-associated vasculitis (AAV) have not been established so far. This study aims to estimate the effects of IVIG on AAV by conducting a systematic review and meta-analysis. METHODS A comprehensive systematic review was conducted in accordance with the guidelines of PRISMA (Preferred Reporting Items for Systematic Reviews And Meta-analyses). PubMed and Google Scholar were used to search for original studies on AAV and collect clinical data before and after IVIG treatment. A meta-analysis of each clinical parameter was performed, and standardized mean difference (SMD) and 95% CI were calculated using the random effects model. RESULTS A total of 220 studies were identified, and nine met the selection criteria for the meta-analysis. IVIG was administered to active AAV patients as an immunomodulatory therapy in the nine studies selected. Significant reductions in BVAS (SMD -1.7; 95% CI [-2.66, -0.73]; P = 0.0006), ANCA (SMD -0.72; 95% CI [-1.13, -0.31]; P = 0.0006) and CRP (SMD -0.92; 95% CI [-1.49, -0.35]; P = 0.002) were noted within 6 months after administration of IVIG. Subgroup analysis in the unmodified immunotherapy population showed reductions in BVAS (SMD -1.39; 95% CI [-2.31, -0.48]; P = 0.003) and CRP (SMD -0.56; 95% CI [-0.93, -0.19]; P = 0.002) within half a month after IVIG treatment. CONCLUSION IVIG was associated with rapid improvements in disease activity and the related biomarkers in patients with active AAV.