Immunoglobulin for multifocal motor neuropathy
The Cochrane database of systematic reviews. 2022;1(1):Cd004429
BACKGROUND Multifocal motor neuropathy (MMN) is a rare, probably immune-mediated disorder characterised by slowly progressive, asymmetric, distal weakness of one or more limbs with no objective loss of sensation. It may cause prolonged periods of disability. Treatment options for MMN are few. People with MMN do not usually respond to steroids or plasma exchange. Uncontrolled studies have suggested a beneficial effect of intravenous immunoglobulin (IVIg). This is an update of a Cochrane Review first published in 2005, with an amendment in 2007. We updated the review to incorporate new evidence. OBJECTIVES To assess the efficacy and safety of intravenous and subcutaneous immunoglobulin in people with MMN. SEARCH METHODS We searched the following databases on 20 April 2021: the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and WHO ICTRP for randomised controlled trials (RCTs) and quasi-RCTs, and checked the reference lists of included studies. SELECTION CRITERIA We considered RCTs and quasi-RCTs examining the effects of any dose of IVIg and subcutaneous immunoglobulin (SCIg) in people with definite or probable MMN for inclusion in the review. Eligible studies had to have measured at least one of the following outcomes: disability, muscle strength, or electrophysiological conduction block. We used studies that reported the frequency of adverse effects to assess safety. DATA COLLECTION AND ANALYSIS Two review authors independently reviewed the literature searches to identify potentially relevant trials, assessed risk of bias of included studies, and extracted data. We followed standard Cochrane methodology. MAIN RESULTS Six cross-over RCTs including a total of 90 participants were suitable for inclusion in the review. Five RCTs compared IVIg to placebo, and one compared IVIg to SCIg. Four of the trials comparing IVIg versus placebo involved IVIg-naive participants (induction treatment). In the other two trials, participants were known IVIg responders receiving maintencance IVIg at baseline and were then randomised to maintenance treatment with IVIg or placebo in one trial, and IVIg or SCIg in the other. Risk of bias was variable in the included studies, with three studies at high risk of bias in at least one risk of bias domain. IVIg versus placebo (induction treatment): three RCTs including IVIg-naive participants reported a disability measure. Disability improved in seven out of 18 (39%) participants after IVIg treatment and in two out of 18 (11%) participants after placebo (risk ratio (RR) 3.00, 95% confidence interval (CI) 0.89 to 10.12; 3 RCTs, 18 participants; low-certainty evidence). The proportion of participants with an improvement in disability at 12 months was not reported. Strength improved in 21 out of 27 (78%) IVIg-naive participants treated with IVIg and one out of 27 (4%) participants who received placebo (RR 11.00, 95% CI 2.86 to 42.25; 3 RCTs, 27 participants; low-certainty evidence). IVIg treatment may increase the proportion of people with resolution of at least one conduction block; however, the results were also consistent with no effect (RR 7.00, 95% CI 0.95 to 51.70; 4 RCTs, 28 participants; low-certainty evidence). IVIg versus placebo (maintenance treatment): a trial that included participants on maintenance IVIg treatment reported an increase in disability in 17 out of 42 (40%) people switching to placebo and seven out of 42 (17%) remaining on IVIg (RR 2.43, 95% CI 1.13 to 5.24; 1 RCT, 42 participants; moderate-certainty evidence) and a decrease in grip strength in 20 out of 42 (48%) participants after a switch to placebo treatment compared to four out of 42 (10%) remaining on IVIg (RR 0.20, 95% CI 0.07 to 0.54; 1 RCT, 42 participants; moderate-certainty evidence). Adverse events, IVIg versus placebo (induction or maintenance): four trials comparing IVIg and placebo reported adverse events, of which data from two studies could be meta-analysed. Transient side effects were reported in 71% of IVIg-treated participants versus 4.8% of placebo-treated participants in these studies. The pooled RR for the development of side effects was 10.33 (95% CI 2.15 to 49.77; 2 RCTs, 21 participants; very low-certainty evidence). There was only one serious side effect (pulmonary embolism) during IVIg treatment. IVIg versus SCIg (maintenance treatment): the trial that compared continuation of IVIg maintenance versus SCIg maintenance did not measure disability. The evidence was very uncertain for muscle strength (standardised mean difference 0.08, 95% CI -0.84 to 1.00; 1 RCT, 9 participants; very low-certainty evidence). The evidence was very uncertain for the number of people with side effects attributable to treatment (RR 0.50, 95% CI 0.18 to 1.40; 1 RCT, 9 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS Low-certainty evidence from three small RCTs shows that IVIg may improve muscle strength in people with MMN, and low-certainty evidence indicates that it may improve disability; the estimate of the magnitude of improvement of disability has wide CIs and needs further studies to secure its significance. Based on moderate-certainty evidence, it is probable that most IVIg responders deteriorate in disability and muscle strength after IVIg withdrawal. SCIg might be an alternative treatment to IVIg, but the evidence is very uncertain. More research is needed to identify people in whom IVIg withdrawal is possible and to confirm efficacy of SCIg as an alternative maintenance treatment.
Furosemide and albumin for the treatment of nephrotic edema: a systematic review
Pediatric nephrology (Berlin, Germany). 2022
BACKGROUND Edema is one of the cardinal clinical features of nephrotic syndrome (NS). It may vary from mild periorbital edema to severe generalized edema (anasarca). In patients where edema does not improve with prednisone therapy, the most common supportive medications are diuretics and albumin. However, due to the complex pathophysiology of edema formation in NS patients resulting in intravascular normovolemia or hypovolemia, optimal therapy for edema is still debated. We conducted a systematic review with the objective of evaluating the change in urine volume and urine sodium excretion after treatment with furosemide only versus furosemide with albumin in edematous patients with NS. OBJECTIVES (1) To evaluate efficacy of furosemide alone versus furosemide with albumin in the treatment of nephrotic edema in adults and children. (2) To compare the harms and benefits of different doses of furosemide for treating nephrotic edema. SEARCH METHODS The search included all randomized or quasi-randomized controlled trials in English and French using MEDLINE, Embase, and CENTRAL Trials Registry of the Cochrane Collaboration using the Ovid interface. ClinicalTrials.gov and the International Clinical Trials Registry Platform were also searched. SELECTION CRITERIA We included all RCTs and randomized cross-over studies in which furosemide and furosemide plus albumin are used in the treatment of children or adults with nephrotic edema. We excluded patients with hypoalbuminemia of non-renal origin and severe chronic kidney disease (CKD) with a glomerular filtration rate below 30 ml/min/1.74 m(2) and patients with congenital NS. DATA COLLECTION AND ANALYSIS All abstracts were independently assessed by at least two authors to determine which studies met the inclusion criteria. Information on study design, methodology, and outcome data (urine volume, urine sodium excretion, adverse effects) from each identified study was entered into a separate data sheet. The differences in outcomes between the types of therapy were expressed as standardized mean difference (SMD) with 95% confidence intervals (CI). RESULTS The search yielded 525 records, and after screening, five studies were included in the systematic review and four of those studies in the meta-analysis. One study had high risk of bias and the remaining three studies were deemed to have some concerns. Urine excretion was greater after treatment with furosemide and albumin versus furosemide (SMD 0.85, 95% CI = 0.33 to 1.38). Results for sodium excretion were inconclusive (SMD 0.37, 95%CI = - 0.28 to 1.02). AUTHORS' CONCLUSIONS The current evidence is not sufficient to make definitive conclusions about the role of albumin in treating nephrotic edema. High-quality randomized studies with adequate samples sizes are needed. Including an assessment of intravascular volume status may be helpful. TRIAL REGISTRATION Prospero: CRD4201808979. https://www.crd.york.ac.uk/PROSPERO A higher resolution version of the Graphical abstract is available as Supplementary information.
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.
Randomized trial of three IVIg doses for treating chronic inflammatory demyelinating polyneuropathy
Brain : a journal of neurology. 2022
Intravenous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy usually starts with a 2.0 g/kg induction dose followed by 1.0 g/kg maintenance doses every 3 weeks. No dose-ranging studies with intravenous immunoglobulin maintenance therapy have been published. The Progress in Chronic Inflammatory Demyelinating polyneuropathy (ProCID) study was a prospective, double-blind, randomised, parallel-group, multicentre, phase III study investigating the efficacy and safety of 10% liquid intravenous immunoglobulin (panzyga®) in patients with active chronic inflammatory demyelinating polyneuropathy. Patients were randomised 1:2:1 to receive the standard intravenous immunoglobulin induction dose and then either 0.5, 1.0 or 2.0 g/kg maintenance doses every 3 weeks. The primary endpoint was the response rate in the 1.0 g/kg group, defined as an improvement ≥ 1 point in adjusted Inflammatory Neuropathy Cause and Treatment score at Week 6 versus baseline and maintained at Week 24. Secondary endpoints included dose response and safety. This trial was registered with EudraCT (Number 2015-005443-14) and clinicaltrials.gov (NCT02638207). Between August 2017 and September 2019, the study enrolled 142 patients. All 142 were included in the safety analyses. As no post infusion data were available for three patients, 139 were included in the efficacy analyses, of whom 121 were previously on corticosteroids. The response rate was 80% (55/69 patients) (95% confidence interval: 69-88%) in the 1.0 g/kg group, 65% (22/34; confidence interval: 48-79%) in the 0.5 g/kg group, and 92% (33/36; confidence interval 78-97%) in the 2.0 g/kg group. While the proportion of responders was higher with higher maintenance doses, logistic regression analysis showed that the effect on response rate was driven by a significant difference between the 0.5 and 2.0 g/kg groups, whereas the response rates in the 0.5 and 2.0 g/kg groups did not differ significantly from the 1.0 g/kg group. Fifty-six percent of all patients had an adjusted Inflammatory Neuropathy Cause and Treatment score improvement 3 weeks after the induction dose alone. Treatment-related adverse events were reported in 16 (45.7%), 32 (46.4%) and 20 (52.6%) patients in the 0.5, 1.0 and 2.0 g/kg dose groups, respectively. The most common adverse reaction was headache. There were no treatment-related deaths. Intravenous immunoglobulin 1.0 g/kg was efficacious and well tolerated as maintenance treatment for patients with chronic inflammatory demyelinating polyneuropathy. Further studies of different maintenance doses of intravenous immunoglobulin in chronic inflammatory demyelinating polyneuropathy are warranted.
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.
Analysis of Relapse by Inflammatory Rasch-built Overall Disability Scale Status in the PATH Study of Subcutaneous Immunoglobulin in Chronic Inflammatory Demyelinating Polyneuropathy
Journal of the peripheral nervous system : JPNS. 2022
BACKGROUND AND AIMS Clinical trials in chronic inflammatory demyelinating polyneuropathy (CIDP) often assess efficacy using the ordinal Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. Here, data from the PATH study was reanalyzed using change in Inflammatory Rasch-built Overall Disability Scale (I-RODS) to define CIDP relapse instead of INCAT. METHODS The PATH study comprised an intravenous immunoglobulin (IVIG) dependency period and an IVIG (IgPro10 [Privigen®]) restabilization period; subjects were then randomized to weekly maintenance subcutaneous immunoglobulin (SCIG; IgPro20 [Hizentra®]) 0.2 g/kg or 0.4 g/kg or placebo for 24 weeks. CIDP relapse was defined as ≥1-point deterioration in adjusted INCAT, with a primary endpoint of relapse or withdrawal rates. This retrospective exploratory analysis redefined relapse using I-RODS via three different cut-off methods: an individual variability method, fixed cut-off of ≥8-point deterioration on I-RODS centile score or ≥4-point deterioration on I-RODS raw score. RESULTS Relapse or withdrawal rates were 47% for placebo, 34% for 0.2 g/kg IgPro20 and 19% for 0.4 g/kg IgPro20 using the raw score; 40%, 28% and 15%, respectively using the centile score, and 49%, 40% and 27%, respectively using the individual variability method. INTERPRETATION IgPro20 was shown to be efficacious as a maintenance therapy for CIDP when relapse was defined using I-RODS. A stable response pattern was shown for I-RODS across various applied cut-offs, indicating that any could be used in future clinical trials.
Phase 2 Study of Avatrombopag in Japanese Patients with Chronic Liver Disease and Thrombocytopenia
Hepatology research : the official journal of the Japan Society of Hepatology. 2022
AIM: Avatrombopag, a thrombopoietin receptor agonist, can reduce the need for platelet transfusions or rescue interventions for bleeding in patients with chronic liver disease (CLD) and thrombocytopenia undergoing scheduled procedures. A model analysis indicated that the effect of avatrombopag on platelet production was reduced in East Asian versus non-East Asian patients; however, the difference was deemed not clinically significant. Furthermore, a subgroup analysis of pooled Phase 3 trials showed similar avatrombopag efficacy across racial subgroups. The aim of this Phase 2 study was to corroborate the efficacy and safety of avatrombopag in Japanese patients with thrombocytopenia due to CLD. METHODS Japanese patients with CLD and thrombocytopenia were randomized to receive placebo or avatrombopag 20, 40, or 60 mg daily for 5 days. The primary endpoint was responder rate in platelet counts at Visit 4 (10-13 days after treatment initiation), defined as the proportion of patients with platelet count ≥50×10(9) /L and ≥20×10(9) /L increase from baseline. RESULTS Thirty-nine patients were randomized and completed the study (placebo, n=11; avatrombopag 20 mg, n=7; 40 mg, n=11; 60 mg, n=10). Avatrombopag treatment was associated with significant increases in responder rate at Visit 4 in the 40 mg (63.6%; P=0.004) and 60 mg (40%; P=0.024) groups versus placebo (9.1%). Avatrombopag was well tolerated and no new safety signals were detected. CONCLUSIONS Efficacy and safety results from this study were consistent with previous studies in patients with CLD and thrombocytopenia undergoing elective procedures, supporting treatment with avatrombopag in the Japanese population. ClinicalTrials.gov identifier: NCT02227693. This article is protected by copyright. All rights reserved.
Effect of oseltamivir phosphate versus placebo on platelet recovery and plasma leakage in adults with dengue and thrombocytopenia; a phase 2, multicenter, double-blind, randomized trial
PLoS neglected tropical diseases. 2022;16(1):e0010051
BACKGROUND Thrombocytopenia, bleeding and plasma leakage are major complications of dengue. Activation of endogenous sialidases with desialylation of platelets and endothelial cells may underlie these complications. We aimed to assess the effects of the neuraminidase inhibitor oseltamivir on platelet recovery and plasma leakage in dengue. METHODS We performed a phase 2, double-blind, multicenter, randomized trial in adult dengue patients with thrombocytopenia (<70,000/μl) and a duration of illness ≤ 6 days. Oseltamivir phosphate 75mg BID or placebo were given for a maximum of five days. Primary outcomes were the time to platelet recovery (≥ 100,000/μl) or discharge from hospital and the course of measures of plasma leakage. RESULTS A total of 70 patients were enrolled; the primary outcome could be assessed in 64 patients (31 oseltamivir; 33 placebo). Time to platelet count ≥100,000/μl (n = 55) or discharge (n = 9) were similar in the oseltamivir and placebo group (3.0 days [95% confidence interval, 2.7 to 3.3] vs. 2.9 days [2.5 to 3.3], P = 0.055). The kinetics of platelet count and parameters of plasma leakage (gall bladder thickness, hematocrit, plasma albumin, syndecan-1) were also similar between the groups. DISCUSSION In this trial, adjunctive therapy with oseltamivir phosphate had no effect on platelet recovery or plasma leakage parameters. TRIAL REGISTRATION ISRCTN35227717.
Pharmacological treatment in adult patients with CRPS-I: A systematic review and meta-analysis of randomised controlled trials
Rheumatology (Oxford, England). 2022
OBJECTIVE Several pharmacological treatments have been proposed for the treatment of Complex regional pain syndrome type-I (CRPS-I) in adults, but data regarding the efficacy of various agents for this disease is scarce. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to analyse pharmacological approaches in adults with CRPS-I. METHODS We systematically searched PubMed, Scopus, and Web of Science databases from the inception date to 30, June 2021 for identifying placebo-controlled or active-controlled RCTs using bisphosphonates, ketamine, corticosteroids, anti-epileptics, NSAIDs/COXIBs, opiates, antidepressants, scavengers/magnesium sulphate or intravenous immunoglobulins for the treatment of CRPS-I. The primary outcomes included changes in the visual analogue scale (VAS) or numeric rating scale (NRS) for pain before and after treatment. RESULTS We included 20 placebo-controlled or active-controlled RCTs (for a total of 818 CRPS-I adults) that used bisphosphonates (n = 7), ketamine (n = 2), corticosteroids (n = 2), anti-epileptics (n = 1), NSAIDs/COXIBs (n = 2), scavengers/magnesium (n = 5), or intravenous immunoglobulins (n = 1) to treat CRPS-I during a median follow-up of 26 weeks. The treatment with bisphosphonates showed a significant reduction of the values of the VAS/NRS pain scale compared with placebo or reference therapy (random effects weighted mean difference [WMD]: -23.8, 95%CI-28.0 to -19.6; I2=36.4%). Treatment with ketamine also documented a reduction in the values of the VAS/NRS pain scale (random effects WMD: -8.27,95%CI -12.9 to -3.70; I2=0%). Treatment with other agents did not improve the values of the VAS/NRS pain scale. CONCLUSION This systematic review and meta-analysis supports the recommendation of parenteral bisphosphonates as the first-line agent in the treatment of CRPS-I. REGISTRATION NUMBER Open Science Framework registries; osf.io/et9gu.
COVID-19 associated vasculitis: A systematic review of case reports and case series
Annals of medicine and surgery (2012). 2022;:103249
Vasculitis is one of the complications of COVID-19. We conducted a systematic review analysing the association of COVID-19 with vasculitis. We searched Google Scholar and PubMed from December 1, 2019, to October 11, 2021. The review included 8 studies (7 case reports and 1 case series) reporting 9 cases of vasculitis secondary to COVID-19. The mean age was 29.17 ± 28.2 years, ranging from 6 months to 83 years. The male to female ratio was 4:5. Maculopapular, violaceous, papular and erythematous rash were common. Heparin(n = 2), corticosteroids (n = 6) (methylprednisolone) and intravenous immunoglobulin (n = 4) were prescribed in these patients. Significant clinical improvement was observed in 8 out of 9 patients. One person died during treatment. Our study discusses vasculitis as one of the complications of COVID-19. Furthermore, the pathophysiology, clinical presentation, and management of COVID-19 associated vasculitis is discussed.