scholarly journals Neurological update: treatment escalation in multiple sclerosis patients refractory to fingolimod—potentials and risks of subsequent highly active agents

2022 ◽  
Author(s):  
Melanie Korsen ◽  
Steffen Pfeuffer ◽  
Leoni Rolfes ◽  
Sven G. Meuth ◽  
Hans-Peter Hartung
Keyword(s):  
Real World ◽  
Washout Period ◽  
Immune Cell ◽  
Absolute Lymphocyte Count ◽  
Relevant Information ◽  
Critical Issue ◽  
Therapeutic Agents ◽  
Increased Risk ◽  
Multiple Sclerosis Patients

AbstractA critical issue in the management of relapsing MS (RMS) is the discontinuation of disease-modifying treatments (DMT) due to lack of efficacy, intolerability or impending risks. With new therapeutic agents introduced into the treatment of RMS, immediate- and long-term consequences of sequential drug use, as well as the effect of the sequence in which the drugs are given, are unclear but may affect efficacy, adverse events, and long-term immunocompetence. In the absence of clinical studies specifically addressing these concerns, observations from clinical practice are of particular value in guiding current management algorithms. Prompted by a study published by Ferraro et al. in this journal, we set out to provide an overview of the published real-world evidence on the effectiveness and safety of switching from fingolimod to another DMT in patients with active RMS. Seventeen publications reporting relevant information were identified. The literature suggests that immune cell depletion induced by alemtuzumab or ocrelizumab is associated with an increased risk of relapse and worsening disability in patients switching from fingolimod compared to patients switching from other therapeutic agents. However, the evidence reported for natalizumab and cladribine is inconclusive. While shortening of the washout period may limit early disease reactivation after fingolimod discontinuation, there is no strong evidence that the duration of the washout period or the absolute lymphocyte count at baseline are predictors of attenuated long-term efficacy. Further real-world studies are required to better understand outcomes among patients who are under-represented in controlled trials.

scholarly journals Real-World Lab Data in Natalizumab Treated Multiple Sclerosis Patients Up to 6 Years Long-Term Follow Up

2018 ◽  
Vol 9 ◽  
Author(s):  
Maxi Kaufmann ◽  
Rocco Haase ◽  
Undine Proschmann ◽  
Tjalf Ziemssen ◽  
Katja Akgün
Keyword(s):  
Multiple Sclerosis ◽  
Real World ◽  
Long Term Follow Up ◽  
Multiple Sclerosis Patients

An excessive risk of suicide may no longer be a reality for multiple sclerosis patients

2017 ◽  
Vol 23 (6) ◽  
pp. 864-871 ◽  
Author(s):  
Shoshannah Kalson-Ray ◽  
Gilles Edan ◽  
Emmanuelle Leray ◽  
Keyword(s):  
Multiple Sclerosis ◽  
General Population ◽  
Population Based ◽  
Sensitivity Analyses ◽  
Clinical Onset ◽  
Increased Risk ◽  
Multiple Sclerosis Patients ◽  
Mean Time ◽  
Long Term Mortality

Background: Few recent studies have shown that there is no longer an increased risk of suicide in patients affected with multiple sclerosis (MS). Objectives: To describe suicide cases within a large French MS cohort and assess whether MS patients are at a higher risk of suicide compared with the general population. Methods: Data derives from a study on long-term mortality of 27,603 prevalent cases from 15 MS specialist centres. Of 1,569 deceased MS patients (5.7%) on 1 January 2010, 47 were suicides. Results: The mean time between MS clinical onset and death was 13.5 years (standard deviation (SD): 9.3 years; none within the first 3 years) and was significantly shorter than for MS patients who had died from other causes (mean = 21.4 (SD = 11.6), p < 0.0001). Age at death was also lower (46.3 vs 56.7). The standardized mortality rates were around 1 in several sensitivity analyses, reflecting no excess mortality in MS compared with general population. Conclusion: Our findings indicate that an excess suicide risk may no longer be true for MS patients and highlight the changing profile of cases, occurring later in the disease course. Further studies in population-based registries are needed to confirm and explain these potential changes (e.g. treatments’ impact?).

scholarly journals The Impact of Successful Chronic Total Occlusion Percutaneous Coronary Intervention on Long-Term Clinical Outcomes in Real World

2020 ◽  
Author(s):  
Xuhe Gong ◽  
Li Zhou ◽  
Xiaosong Ding ◽  
Hui Chen ◽  
Hongwei Li
Keyword(s):  
Percutaneous Coronary Intervention ◽  
Coronary Artery ◽  
Clinical Outcomes ◽  
Real World ◽  
Cardiac Death ◽  
Coronary Intervention ◽  
Increased Risk ◽  
Percutaneous Coronary ◽  
The Impact

Abstract Background: Coronary chronic total occlusions (CTOs) are correlated with increased risk of adverse clinical outcomes. The optimal treatment strategy for CTO has not been well established. We sought to examine the impact of CTO percutaneous coronary intervention (PCI) on long-term clinical outcome in the real world.Methods: A total of 592 consecutive patients with CTO in Beijing Friendship Hospital from June 2017 to December 2019 were enrolled, 29 patients were excluded due to Coronary artery bypass grafting (CABG). After exclusion, 563 patients were divided into the no-revascularized group (CTO-NR group, n=263) and successful revascularized group (CTO-R group, n=300). The primary endpoint was cardiac death; Secondary endpoint was major adverse cardiac and cerebrovascular events (MACCE), a composite of all-cause death, cardiac death, recurrent myocardial infarction, target lesion revascularization, re-hospitalization, heart failure, and stroke.Results: Percent of Diabetes mellitus (53.2% vs 39.7), Chronic kidney disease (8.7% vs 3.7%), CABG history (7.6% vs 1%), three vessel disease(96.2% vs 90%) and left main coronary artery disease (25.1% vs 13.7%) was significantly higher in the CTO-NR group than in success PCI group (all P<0.05). Moreover, the CTO-NR group has lower EF (0.58±0.11 vs 0.61±0.1, p=0.001) and FS (0.31±0.07 vs 0.33±0.07, p=0.002). At a median follow-up of 12 months, CTO revascularization was superior to CTO no-revascularization in terms of cardiac death (adjusted hazard ratio [HR]: 0.27, 95% conference interval [CI] 0.11-0.64). The superiority of CTO revascularization was consistent for MACCE (HR: 0.55, 95% CI 0.35-0.79). At multivariable Cox hazards regression analysis, CTO revascularization remains one of the independent predictors of lower risk of cardiac death and MACCE.Conclusions: Successful revascularization by PCI may bring more clinical benefits. The presence of LVEF＜0.5 and LM-disease was associated with an incidence of cardiac death; CTO revascularization was a protected predictor of cardiac death.

scholarly journals Lymphocyte counts and infection rates

2019 ◽  
Vol 6 (6) ◽  
pp. e614 ◽  
Author(s):  
Edward J. Fox ◽  
Fred D. Lublin ◽  
Jerry S. Wolinsky ◽  
Jeffrey A. Cohen ◽  
Ian M. Williams ◽  
...  
Keyword(s):  
Secondary Analysis ◽  
Absolute Lymphocyte Count ◽  
Term Treatment ◽  
Upper Respiratory Tract ◽  
Infection Rates ◽  
Double Blind ◽  
Increased Risk ◽  
Long Term Treatment ◽  
Tract Infections

ObjectiveTo evaluate lymphocyte counts and incidences of infections in patients with primary progressive MS (PPMS) receiving fingolimod 0.5 mg/d or placebo over 5 years during the INFORMS study, to assess infection rates with longer-term treatment.MethodsINFORMS was a randomized, multicenter, double-blind, placebo-controlled, parallel-group, phase 3 study of the sphingosine 1-phosphate receptor modulator fingolimod in patients with PPMS. Lymphocyte counts and incidences of infections were compared in patients receiving fingolimod or placebo. Infection rates were assessed in patients receiving fingolimod according to nadir and mean absolute lymphocyte count (ALC).ResultsOverall, 336 patients received fingolimod 0.5 mg/d (total exposure: 908.1 patient-years), and 487 received placebo (1,423.5 patient-years). In patients receiving fingolimod, mean ALC decreased by approximately 70% in the 2 weeks following treatment initiation and remained stable throughout the study. The incidences of all infections in the fingolimod and placebo groups were similar (53.6 vs 51.9 per 100 patient-years). The most common infections in patients receiving fingolimod were urinary tract infections (5.7 per 100 patient-years), upper respiratory tract infections (4.2 per 100 patient-years), and influenza (3.2 per 100 patient-years); incidences were similar in the placebo group (5.9, 4.2, and 3.1 per 100 patient-years, respectively). There was no apparent association between nadir or mean ALC and incidence of infection-related adverse events.ConclusionsIn patients with PPMS, long-term treatment with fingolimod 0.5 mg/d for up to 5 years led to an expected decrease of approximately 70% in mean ALC and did not appear to correlate with increased risk of infection.Classification of evidenceBecause this is a secondary analysis, this study provides Class II evidence that long-term PPMS treatment with fingolimod decreased mean ALC by approximately 70%, but did not significantly increase infection risk.

scholarly journals Evidence for Persistent Monocyte and Immune Dysregulation After Prolonged Viral Suppression Despite Normalization of Monocyte Subsets, sCD14 and sCD163 in HIV-Infected Individuals

2019 ◽  
Vol 4 (2) ◽  
pp. 324 ◽  
Author(s):  
Anjana Yadav ◽  
Andrew V. Kossenkov ◽  
Vincent R. Knecht ◽  
Louise C. Showe ◽  
Sarah J. Ratcliffe ◽  
...  
Keyword(s):  
Immune Cell ◽  
Immune Dysregulation ◽  
People Living With Hiv ◽  
Older Individuals ◽  
Immune Functions ◽  
Elevated Plasma ◽  
Monocyte Subsets ◽  
Increased Risk ◽  
Plasma Cytokines

Background: People living with HIV on antiretroviral therapy (HIV/ART) experience excess non-AIDS comorbidities, and also remain at increased risk for certain infections and viral malignancies. Monocytes/macrophages are central to many of these comorbidities, and elevated plasma cytokines and immune activation during untreated infection are often incompletely reversed by ART and are also associated with comorbidities.Methods: We investigated monocyte surface markers, gene expression, and plasma cytokines in 11 HIV-infected older individuals (median 53 years) who started therapy with low CD4 counts (median 129 cells/μl), with elevated hsCRP (≥ 2mg/L) despite long-term ART (median 7.4 years), along with matched controls.Results: Frequency of monocyte subsets (based on CD14/CD16/CD163), were not different from controls, but surface expression of CD163 was increased (P = 0.021) while PD1 was decreased (P = 0.013) along with a trend for higher tissue factor (P = 0.096). As a group, HIV/ART participants had elevated plasma CCL2 (MCP-1; P = 0.0001), CXCL9 (MIG; P = 0.04), and sIL2R (P = 0.015), which were correlated, while sCD14 was not elevated. Principal component analysis of soluble markers revealed that 6/11 HIV/ART participants clustered with controls, while 5 formed a distinct group, driven by IL-10, CCL11, CXCL10, CCL2, CXCL9, and sIL2R. These individuals were significantly older than those clustering with controls. Transcriptomic analysis revealed multiple genes linked to immune functions including inflammation, immune cell development, and cell-cell signaling that were downregulated in HIV/ART monocytes and distinct from patterns in untreated subjects.Conclusions: Long-term ART-treated individuals normalize monocyte subsets but exhibit immune dysregulation involving both aberrant inflammation and monocyte dysfunction, as well as inter-individual heterogeneity, suggesting complex mechanisms linking monocytes and HIV/ART comorbidities.

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