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American Journal of Transplantation :... Apr 2019Low T cell counts and acute rejection are associated with increased cardiovascular events (CVEs); T cell-depleting agents decrease both. Thus, we aimed to characterize...
Low T cell counts and acute rejection are associated with increased cardiovascular events (CVEs); T cell-depleting agents decrease both. Thus, we aimed to characterize the risk of CVEs by using an induction agent used in kidney transplant recipients. We conducted a secondary data analysis of patients who received a kidney transplant and used Medicare as their primary insurance from 1999 to 2010. Outcomes of interest were incident CVE, all-cause mortality, CVE-related mortality, and a composite outcome of mortality and CVE. Of 47 258 recipients, 29.3% received IL-2 receptor antagonist (IL-2RA), 33.3% received anti-thymocyte globulin (ATG), 7.3% received alemtuzumab, and 30.0% received no induction. Compared with IL-2RA, there was no difference in the risk of CVE in the ATG (adjusted hazard ratio [aHR] 0.98, 95% confidence interval [CI] 0.92-1.05) and alemtuzumab group (aHR 1.01, 95% CI 0.89-1.16), but slightly higher in the no induction group (aHR 1.06, 95% CI 1.00-1.14). Acute rejection did not modify this association in the latter group but did increase CVE by 46% in the alemtuzumab group. There was no difference in the hazard of all-cause or CVE-related mortality. Only in the ATG group, a 7% lower hazard of the composite outcome of mortality and CVE was noted. Induction agents are not associated with incident CVE, although prospective trials are needed to determine a personalized approach to prevention.
Topics: Cardiovascular Diseases; Female; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Transplantation; Male; Middle Aged; Risk Factors
PubMed: 30372596
DOI: 10.1111/ajt.15148 -
Neurology Nov 2018To characterize the use and safety of newer disease-modifying therapies (DMTs) in children with multiple sclerosis (MS) and clinically isolated syndrome (CIS) treated... (Observational Study)
Observational Study
OBJECTIVE
To characterize the use and safety of newer disease-modifying therapies (DMTs) in children with multiple sclerosis (MS) and clinically isolated syndrome (CIS) treated under 18 years of age.
METHODS
This is a cohort study including children with MS or CIS followed at 12 outpatient practices participating in the US Network of Pediatric MS Centers. DMT use, including duration, dose, and side effects, was analyzed. Newer DMTs were defined as agents receiving Food and Drug Administration approval or with increased use in adult MS after 2005.
RESULTS
As of July 2017, 1,019 pediatric patients with MS (n = 748) or CIS (n = 271) were enrolled (65% female, mean onset 13.0 ± 3.9 years, mean follow-up 3.5 ± 3.1 years, median 1.6 visits per year). Of these, 78% (n = 587) with MS and 11% (n = 31) with CIS received DMT before 18 years of age. This consisted of at least one newer DMT in 42%, including dimethyl fumarate (n = 102), natalizumab (n = 101), rituximab (n = 57), fingolimod (n = 37), daclizumab (n = 5), and teriflunomide (n = 3). Among 17%, the initial DMT prescribed was a newer agent (36 dimethyl fumarate, 30 natalizumab, 22 rituximab, 14 fingolimod, 2 teriflunomide). Over the last 10 years, the use of newer agents has increased, particularly in those ≥12 years and to lesser extent in those <12 years. The short-term side effect profiles of newer DMTs did not differ from those reported in adults.
CONCLUSION
Newer DMTs are often used in pediatric MS, and have similar short-term safety, tolerability, and side effect profiles as in adults. These findings may help inform pediatric MS management.
Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Female; Humans; Immunosuppressive Agents; Male; Multiple Sclerosis; Practice Patterns, Physicians'; United States
PubMed: 30333163
DOI: 10.1212/WNL.0000000000006471 -
PharmacoEconomics Mar 2019As part of the single technology appraisal process, the National Institute for Health and Care Excellence invited Merck to submit evidence for the clinical and cost... (Review)
Review
As part of the single technology appraisal process, the National Institute for Health and Care Excellence invited Merck to submit evidence for the clinical and cost effectiveness of cladribine tablets (cladribine) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Rapidly evolving severe (RES) and sub-optimally treated (SOT) RRMS were specified by the National Institute for Health and Care Excellence as subgroups of interest. The Liverpool Reviews and Implementation Group at the University of Liverpool was the Evidence Review Group. This article summarises the Evidence Review Group's review of the company's evidence submission for cladribine and the Appraisal Committee's final decision. The final scope issued by the National Institute for Health and Care Excellence listed the following disease-modifying treatments as comparators: alemtuzumab, daclizumab, fingolimod and natalizumab. At the time of the company submission, a licence was anticipated for low-dose cladribine. The main clinical evidence (the CLARITY trial) in the company submission focused on the efficacy of low-dose cladribine vs. placebo. The CLARITY trial showed a statistically significant reduction in relapse rate for cladribine in the RES-RRMS subgroup (n = 50) but not in the SOT-RRMS subgroup (n = 19). Cladribine showed a numerical, but not a statistically significant, advantage in delaying disability progression at 6 months in the RES-RRMS subgroup. Disability progression benefits could not be estimated for those in the SOT-RRMS subgroup because of few events. The Evidence Review Group's main concern regarding the clinical evidence was the small sample size of the subgroups. To compare the effectiveness of cladribine to other disease-modifying treatments, the company conducted network meta-analyses, which showed cladribine and its comparators to be equally effective. The Evidence Review Group considered the results of the disease-modifying treatments to be unreliable because few trials were in the network. The company's cost-effectiveness evidence showed cladribine to be cheaper and more effective than other disease-modifying treatments in the RES-RRMS arm and the SOT-RRMS arm. The results were most sensitive to treatment effect on disability progression at 6 months. The Evidence Review Group was concerned that there was insufficient evidence to conclude that cladribine was superior to placebo in delaying disability progression. The Evidence Review Group amended the company's economic model to allow alternative estimates for the treatment effect of cladribine and its comparators on relapse rate and disability progression at 6 months. The Evidence Review Group made other changes to the company model. After implementing all the amendments, cladribine remained cost effective in the RES-RRMS and SOT-RRMS subgroups. The Appraisal Committee recognised the uncertainty in the available data but concluded that cladribine could be considered a cost-effective use of National Health Service resources.
Topics: Cladribine; Cost-Benefit Analysis; Humans; Immunosuppressive Agents; Models, Economic; Multiple Sclerosis, Relapsing-Remitting; Tablets; Technology Assessment, Biomedical
PubMed: 30328051
DOI: 10.1007/s40273-018-0718-2 -
Frontiers in Neurology 2018Differential diagnosis of neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) or mimics can be challenging, especially in patients with atypical...
Rebound After Fingolimod and a Single Daclizumab Injection in a Patient Retrospectively Diagnosed With NMO Spectrum Disorder-MRI Apparent Diffusion Coefficient Maps in Differential Diagnosis of Demyelinating CNS Disorders.
Differential diagnosis of neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) or mimics can be challenging, especially in patients with atypical presentations and negative serostatus for aquaporin-4 antibodies (AQP4-Ab). This brief research report describes magnetic resonance imaging (MRI) findings focusing on quantitative apparent diffusion coefficient (ADC) histogram analysis as a potential tool to differentiate NMOSD from MS. Longitudinal MRI data obtained during routine clinical examinations were retrospectively analyzed in a patient with histologically determined cerebral NMOSD, a patient with an acute tumefactive MS lesion, and a patient with ischemic stroke. Histogram analyses of ADC maps were evaluated. A patient diagnosed with MS experienced a severe rebound after fingolimod withdrawal and a single daclizumab injection. Cerebral NMOSD manifestation was confirmed by brain biopsy. However, the patient did not fulfill consensus criteria for NMOSD and was AQP4-Ab negative. Comparison of ADC histogram analyses of this patient with those from a patient with MS and one with ischemic stroke revealed differential ADC characteristics: namely a more pronounced and prolonged ADC leftward shift in inflammatory than in ischemic pathology, even more accentuated in NMOSD versus MS. ADC map histograms and ADC threshold values for different conditions may be useful for differentiation of large inflammatory brain lesions and further studies are merited.
PubMed: 30319524
DOI: 10.3389/fneur.2018.00782 -
Journal of Neuroinflammation Sep 2018We compared the magnetic resonance imaging (MRI) features between Japanese and Caucasian patients with multiple sclerosis (MS), and identified the relationships between...
BACKGROUND
We compared the magnetic resonance imaging (MRI) features between Japanese and Caucasian patients with multiple sclerosis (MS), and identified the relationships between MRI features and disability.
METHODS
From the baseline data of phase II fingolimod trials, 95 Japanese and 246 Caucasian relapsing-remitting MS patients were enrolled. The number, volume, and distribution of brain MRI lesions were evaluated using T2-weighted (T2W) images. Cross-sectional total normalized brain volume (NBV), normalized cortical gray matter volume, normalized deep gray matter volume (NDGMV), normalized white matter volume (NWMV), and normalized thalamic volume were measured.
RESULTS
Japanese patients had significantly lower Expanded Disability Status Scale (EDSS) scores than Caucasian patients (mean 2.0 vs. 2.3, p = 0.008), despite a similar disease duration. Japanese patients showed a trend towards fewer T2W-lesions (median 50 vs. 65, p = 0.08) and significantly lower frequencies of cerebellar and parietal lobe lesions (p = 0.02 for both) than Caucasian patients. There were no differences in T2W-lesion volume between races, whereas Japanese patients had a significantly larger T2W-lesion volume per lesion compared with Caucasian patients (median 140 mm vs. 85 mm, p < 0.0001). T2W-lesion volumes were positively correlated with EDSS scores in Japanese patients (p < 0.0001). In both races, NBV, normalized cortical gray matter volume, NDGMV, and thalamic volume were negatively correlated with disease duration and EDSS scores (p < 0.01 for all). NWMV was negatively correlated with disease duration and EDSS scores only in Caucasian patients (p = 0.03 and p = 0.004, respectively). NBV, NDGMV, NWMV, and thalamic volume were consistently smaller in Japanese compared with Caucasian patients throughout the entire examined disease duration (p = 0.046, p = 0.01, p = 0.005, and p = 0.04, respectively). Japanese patients had a significantly faster reduction in NDGMV (p = 0.001), particularly for thalamic volume (p = 0.001), with disease duration compared with Caucasian patients.
CONCLUSIONS
Gray matter atrophy is a common denominator for disability in Japanese and Caucasian patients. Additional contributory factors for disability include T2W-lesion volume in Japanese patients and white matter atrophy in Caucasian patients. Less frequent parietal and cerebellar involvement with fewer T2W-lesions may underlie milder disability in Japanese patients.
Topics: Adult; Brain; Cross-Sectional Studies; Disability Evaluation; Disabled Persons; Disease Progression; Female; Humans; Image Processing, Computer-Assisted; Japan; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Reference Values; Severity of Illness Index; White People
PubMed: 30185189
DOI: 10.1186/s12974-018-1295-1 -
American Journal of Transplantation :... Mar 2019Delayed graft function (DGF) is a risk factor for acute rejection (AR) in renal transplant recipients, and KDIGO guidelines suggest use of lymphocyte-depletion induction...
Delayed graft function (DGF) is a risk factor for acute rejection (AR) in renal transplant recipients, and KDIGO guidelines suggest use of lymphocyte-depletion induction when DGF is anticipated. We analyzed the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) database to assess the impact of induction immunosuppression on the risk of AR in deceased kidney recipients based on pretransplant risk of DGF using a validated model. Recipients were categorized into 4 groups based upon the induction immunosuppression: (1) Rabbit anti-thymocyte globulin (rATG); (2) Alemtuzumab (C1H); (3) IL2-receptor antagonists (IL2-RA; basiliximab or daclizumab), and (4) No antibody induction. The primary endpoint for analysis was a composite endpoint of treated AR or graft failure by 1-year posttransplantation. Compared to no antibody induction, rATG and C1H had consistently lower adjusted odds of the composite endpoint across all risk strata for DGF risk, whereas IL2-Ra was associated with increased adjusted odds of the composite endpoint with increasing DGF risk. When the induction agents were compared, rATG and C1H were associated with decreasing adjusted odds for the composite endpoint with increasing risk of DGF, especially at the higher risk spectrum of DGF. Consideration must be given to use of lymphocyte-depletion induction when the anticipated risk of DGF is increased.
Topics: Adolescent; Adult; Aged; Delayed Graft Function; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Lymphocyte Depletion; Male; Middle Aged; Postoperative Complications; Prognosis; Risk Factors; Transplant Recipients; Young Adult
PubMed: 30171800
DOI: 10.1111/ajt.15102 -
BMJ Open Aug 2018The major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society... (Comparative Study)
Comparative Study Randomized Controlled Trial
Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis.
INTRODUCTION
The major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist); fluoxetine (selective serotonin reuptake inhibitor) and riluzole (glutamate antagonist).
METHODS AND ANALYSIS
Patients with progressing SPMS will be randomised 1:1:1:1 to amiloride, fluoxetine, riluzole or matched placebo and followed for 96 weeks. The primary outcome will be the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalisation, of Atrophy method. With a sample size of 90 per arm, this will give 90% power to detect a 40% reduction in PBVC in any active arm compared with placebo and 80% power to detect a 35% reduction (analysing by analysis of covariance and with adjustment for multiple comparisons of three 1.67% two-sided tests), giving a 5% overall two-sided significance level. MS-SMART is not powered to detect differences between the three active treatment arms. Allowing for a 20% dropout rate, 110 patients per arm will be randomised. The study will take place at Neuroscience centres in England and Scotland.
ETHICS AND DISSEMINATION
MS-SMART was approved by the Scotland A Research Ethics Committee on 13 January 2013 (REC reference: 13/SS/0007). Results of the study will be submitted for publication in a peer-reviewed journal.
TRIAL REGISTRATION NUMBERS
NCT01910259; 2012-005394-31; ISRCTN28440672.
Topics: Adult; Amiloride; Double-Blind Method; Female; Fluoxetine; Humans; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Neuroprotective Agents; Riluzole; Treatment Outcome
PubMed: 30166303
DOI: 10.1136/bmjopen-2018-021944 -
Experimental and Clinical... Aug 2019Immunosuppressive therapy in kidney transplant recipients with hepatitis B virus infection may increase the risk of disease progression. Here, we compared outcomes of... (Comparative Study)
Comparative Study
OBJECTIVES
Immunosuppressive therapy in kidney transplant recipients with hepatitis B virus infection may increase the risk of disease progression. Here, we compared outcomes of depleting (antithymocyte globulin/alemtuzumab) versus nondepleting (basiliximab/daclizumab) antibody induction in kidney transplant recipients at different serologic phases of hepatitis B virus infection.
MATERIALS AND METHODS
We used the Organ Procurement and Transplantation Network/United Network for Organ Sharing database to identify adult kidney transplant recipients at different serologic phases of hepatitis B virus infection (transplants received from 2001-2011 after patients received perioperative induction with discharge on calcineurin inhibitors/mycophenolate mofetil with/without steroids). We used a Cox model to compare outcomes among patient groups.
RESULTS
Median follow-up was 50.7 months (range, 28.6 to 82.6 mo). Serologic phase for the 7681 study patients were as follows: 1098 at HBsAg+/anti-HBc- (depleting = 652, nondepleting = 446), 446 at HBsAg+/anti-HBc+ (depleting = 250, nondepleting = 216), and 6117 at HBsAg-/anti-HBc+ (depleting = 3562, nondepleting = 2555) (where anti-HBc denotes hepatitis B core antibody, HBsAg denotes hepatitis B surface antigen, and +/- denote positive/negative). When we compared those with depleting versus nondepleting agents, hazard ratios (95% confidence intervals) for adjusted overall graft, death-censored graft, and patient survival were 0.97 (0.78-1.26; P = .86), 1.20 (0.83-1.60; P = .44), and 0.92 (0.66-1.30; P = .51) in the HBsAg+/anti-HBc-; 0.81 (0.55-1.18; P = .27), 0.59 (0.32-1.12; P = .11), and 0.95 (0.60-1.49; P = .83) in the HBsAg+/anti-HBc+; and 0.96 (0.86-1.05; P = .37), 0.95 (0.60-1.49; P = .97), and 0.92 (0.80-1.05; P = 0.22) in the HBsAg-/anti-HBc+ groups.
CONCLUSIONS
Our study did not show adverse graft and patient outcomes associated with depleting versus nondepleting antibody induction in kidney transplant recipients at different phases of hepatitis B virus infection. This supports the selection and use of induction agents based on immunologic risk in such patients.
Topics: Adult; Alemtuzumab; Antilymphocyte Serum; Basiliximab; Clinical Decision-Making; Daclizumab; Databases, Factual; Disease Progression; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Young Adult
PubMed: 30066624
DOI: 10.6002/ect.2017.0286 -
Neurology(R) Neuroimmunology &... Sep 2018To describe a case of glial fibrillary acidic protein (GFAP)α immunoglobulin G (IgG)-associated encephalitis in a patient referred to us with MS on daclizumab treatment...
OBJECTIVE
To describe a case of glial fibrillary acidic protein (GFAP)α immunoglobulin G (IgG)-associated encephalitis in a patient referred to us with MS on daclizumab treatment and to summarize characteristics of 5 additional recent German MS cases of serious encephalitis along with a previously published American case of CNS vasculitis associated with daclizumab.
METHODS
Evaluation of cause, clinical symptoms, and treatment response.
RESULTS
The 6 patients included 4 women and 2 men. The median age at onset was 38 years (range 32-51 years). Clinical presentation was marked by progressing neuropsychologic and/or neurologic deficits. Additional drug rash with eosinophilia was seen in 3 patients, whereas 2 patients showed a highly active demyelinating process. Examination of CSF samples detected pleocytosis, elevated total protein levels, and GFAPα IgG antibodies, which were not found in serum. In our case, we discovered autoimmune GFAP astrocytopathy associated with encephalitis as secondary autoimmunity, which was steroid responsive. Clinical outcome of other cases was marked by partial recovery in 4 patients and persistent foster care in 1 patient.
CONCLUSIONS
Our case of GFAPα IgG-associated encephalitis along with 12 other cases of serious inflammatory brain disorders following daclizumab treatment so far indicates that interfering with NK cells and Tregs by anti-CD25 antibody therapy can result in severe secondary CNS autoimmunity in man.
PubMed: 30027106
DOI: 10.1212/NXI.0000000000000481 -
Neurology(R) Neuroimmunology &... Sep 2018
PubMed: 30027105
DOI: 10.1212/NXI.0000000000000479