Autologous haematopoietic stem cell transplantation (AHSCT) is increasingly used as a treatment for aggressive multiple sclerosis (MS) and has the potential to induce long-term remission and ...resolution of disease activity. Despite the extensive research on treatment outcome after AHSCT, the experience of living with MS after AHSCT has not been previously described in the scientific literature. The aim of this study was to explore long-term lived experience of people with MS treated with AHSCT.
To exclude selection bias, all persons treated with AHSCT for MS at Uppsala University Hospital, Sweden, between 2004 and 2007 (n = 10), were asked to participate in the study, and all accepted. Open-ended interviews were conducted, digitally recorded, transcribed verbatim, and then subjected to qualitative content analysis with an inductive approach. Five main themes emerged from the interviews: (I) being diagnosed with MS-an unpredictable existence; (II) a new treatment-a possibility for a new life; (III) AHSCT-a transition; (IV) reclaiming life; and (V) a bright future accompanied by insecurity. AHSCT was described by the participants in terms of a second chance and an opportunity for a new life. The treatment became a transition from a state of illness to a state of health, enabling a previous profound uncertainty to wane and normality to be restored. Although participants of different age and sex were included, the main limitation of this study is the relatively small number of participants. Also, the inclusion of persons from one centre alone could restrict transferability of the results.
The results give a first insight into lived experience following a highly effective induction treatment for MS, and the experience of not having MS anymore. Underpinned by previously described outcome following AHSCT, the results of this study challenge the current view on MS as a chronic disease with no possible cure.
Autologous hematopoietic stem cell transplantation (AHSCT) has been approved for multiple sclerosis (MS) in many European countries. A large proportion of patients are women of child-bearing age. For ...them, AHSCT may have negative consequences for reproductive health, since the ovaries are particularly susceptible to alkylating agents. Anti-Müllerian hormone (AMH) reflects the ovarian reserve and has been suggested as a potential biomarker of fertility in women. The aim of this study was to investigate AMH levels in relation to age and reproductive potential in MS patients treated with AHSCT. The study cohort comprised 38 female patients, aged 20-44 years, who underwent AHSCT for MS using a cyclophosphamide (200 mg/kg)/rabbit-anti-thymocyte globulin (6 mg/kg) conditioning regimen between 2013-2020. Clinal follow-up visits were made 3 months after AHSCT and then yearly. AMH was analysed in blood samples. The median age at transplantation was 28 years (interquartile range, IQR 25-33). The median AMH concentration was 23 pmol/l at baseline (IQR 6.0-30), 0.5 pmol/l at 3 months (IQR 0-1.5) and 1.1 pmol/l at 2 years (IQR 0-2.9). A multiple linear regression model was used to determine if age and/or AHSCT influenced AMH values; both significantly did (age, -0.21 per year, p = 0.018; AHSCT -19, p <0.0001). Seven women became pregnant, six spontaneously and one both spontaneously and with IVF. One patient underwent an abortion, all other pregnancies led to live births. Six of the women became pregnant despite low or very low post-AHSCT serum concentrations of AMH, suggesting that low serum AMH concentrations do not necessarily reflect impaired fertility in patients treated with high-dose cyclophosphamide.
Abstract Galectin-9 is produced by activated astrocytes, induces a pro-inflammatory response in microglia and may be important to the pathogenesis of secondary progressive MS. In this study, ...Galectin-9 concentrations in CSF samples from healthy controls and two independent patient cohorts of MS patients were determined by ELISA. Patients from one of the cohorts underwent MRI as well. Galectin-9 concentrations in CSF were higher in SPMS patients than healthy controls and RRMS patients in both cohorts. Galectin-9 concentrations correlated with the number of lesions on T1-weighted images, but not with gadolinium enhancing lesions, IgG index or CSF cell count.
Abstract YKL-40 (CHI3L1) is a glycoprotein predominantly produced by reactive astrocytes in chronic active MS lesions, which are common in secondary progressive MS. In this study, YKL-40 was ...investigated in different stages of MS and in relation to MRI findings. YKL-40 levels in CSF samples from two independent patient cohorts of MS patients were determined with ELISA. CSF YKL-40 was increased in patients with active relapsing–remitting MS and correlated with the number of gadolinium enhancing lesions. Patients with secondary progressive MS had similar high levels of YKL-40, whereas not active relapsing–remitting MS patients had YKL-40 levels comparable to healthy controls.
Objective
This study aimed to explore the clinical characteristics and temporal disease course of patients with autoimmune encephalitis (AE) and paraneoplastic neurological syndrome (PNS) in Sweden.
...Methods
Thirty‐seven antibody‐positive AE and PNS cases were identified in the Healthcare region Mid Sweden between 2015 and 2019. Clinical data were collected through a retrospective review of electronic health records. Patients were divided into three subgroups based on antibody type: neuronal surface antibodies (NSAbs), onconeural antibodies, and anti‐GAD65 antibodies.
Results
Nineteen patients had NSAbs, 11 onconeural antibodies, and seven anti‐GAD65 antibodies. Anti‐LGI1 and anti‐NMDAR were the most frequently detected NSAbs, with anti‐NMDAR cases having an older‐than‐expected age distribution (median age 40, range 17–72). Only 11 of 32 (30%) of patients had findings suggesting encephalitis on initial MRI, but 28 of 31 (90%) had pathological findings on initial cerebrospinal fluid analysis. All patients but one had abnormal EEG findings. Median time to immunotherapy was comparable among the three subgroups, whereas patients with anti‐LGI1, anti‐CASPR2, and anti‐IgLON5 had an eightfold longer time to immunotherapy than anti‐NMDAR and anti‐GABA‐B (p = .0016). There was a seasonal variation in onset for patients with non‐tumor‐related NSAbs and anti‐GAD65 antibodies, with most patients (72%) falling ill in spring or summer.
Conclusion
Swedish patients with AE and PNS had similar clinical characteristics as previously described cohorts from other geographical regions except for anti‐NMDAR encephalitis, with older onset than expected. The onset of non‐tumor‐related AE occurred predominantly in the warm seasons, and AE with a more insidious onset was associated with delayed treatment initiation.
This case series of 37 patients with autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS) demonstrated that Swedish patients have similar clinical characteristics compared with previously described cohorts from other geographical regions except for anti‐NMDAR encephalitis, with older onset than expected. The onset of non‐tumor‐related AE occurs predominantly in the warm seasons, and AE with a more insidious onset is associated with delayed treatment initiation.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). In the murine experimental autoimmune encephalomyelitis (EAE) model of MS, T regulatory (Treg) cell therapy has ...proved to be beneficial, but generation of stable CNS-targeting Tregs needs further development. Here, we propose gene engineering to achieve CNS-targeting Tregs from naïve CD4 cells and demonstrate their efficacy in the EAE model.
CD4+ T cells were modified utilizing a lentiviral vector system to express a chimeric antigen receptor (CAR) targeting myelin oligodendrocyte glycoprotein (MOG) in trans with the murine FoxP3 gene that drives Treg differentiation. The cells were evaluated in vitro for suppressive capacity and in C57BL/6 mice to treat EAE. Cells were administered by intranasal (i.n.) cell delivery.
The engineered Tregs demonstrated suppressive capacity in vitro and could efficiently access various regions in the brain via i.n cell delivery. Clinical score 3 EAE mice were treated and the engineered Tregs suppressed ongoing encephalomyelitis as demonstrated by reduced disease symptoms as well as decreased IL-12 and IFNgamma mRNAs in brain tissue. Immunohistochemical markers for myelination (MBP) and reactive astrogliosis (GFAP) confirmed recovery in mice treated with engineered Tregs compared to controls. Symptom-free mice were rechallenged with a second EAE-inducing inoculum but remained healthy, demonstrating the sustained effect of engineered Tregs.
CNS-targeting Tregs delivered i.n. localized to the CNS and efficiently suppressed ongoing inflammation leading to diminished disease symptoms.
Huntington's disease (HD) is a neurodegenerative disorder, but evidence also suggests neuroinflammation in the pathogenesis. The immune mechanisms involved and the timing of their activation need ...further clarification.
A clinically well-characterized HD cohort and gene negative controls were enrolled. YKL-40 reflecting innate immunity and sCD27, a marker of adaptive immunity, were measured across disease stages. Comparisons were made with markers of neurodegeneration: neurofilament light (NFL), total-tau (T-tau), and phospho-tau (P-tau).
52 cross-sectional cerebrospinal fluid samples and 23 follow-up samples were analyzed. sCD27 was elevated in manifest HD and premanifest gene expansion carriers, whereas controls mostly had undetectable levels. YKL-40 showed a trend toward increase in manifest HD. sCD27 correlated with YKL-40 which in turn was closely associated to all included markers of neurodegeneration. YKL-40, NFL, and both forms of tau could all independently predict HD symptoms, but only NFL levels differed between groups after age-adjustment.
Increased sCD27 in premanifest HD is a sign of T cell-mediated neuroinflammation. This finding is novel since other reports almost exclusively have found early involvement of innate immunity. Validation of sCD27 in a larger HD cohort is needed. The role of adaptive immunity in HD needs further clarification, as it may hasten disease progression.
Chronic diseases affecting the central nervous system (CNS) like Alzheimer's or Parkinson's disease typically develop with advanced chronological age. Yet, aging at the metabolic level has been ...explored only sporadically in humans using biofluids in close proximity to the CNS such as the cerebrospinal fluid (CSF). We have used an untargeted liquid chromatography high-resolution mass spectrometry (LC-HRMS) based metabolomics approach to measure the levels of metabolites in the CSF of non-neurological control subjects in the age of 20 up to 74. Using a random forest-based feature selection strategy, we extracted 69 features that were strongly related to age (p
< 0.001, r
= 0.762, R
= 0.764). Combining an in-house library of known substances with in silico chemical classification and functional semantic annotation we successfully assigned putative annotations to 59 out of the 69 CSF metabolites. We found alterations in metabolites related to the Cytochrome P450 system, perturbations in the tryptophan and kynurenine pathways, metabolites associated with cellular energy (NAD+, ADP), mitochondrial and ribosomal metabolisms, neurological dysfunction, and an increase of adverse microbial metabolites. Taken together our results point at a key role for metabolites found in CSF related to the Cytochrome P450 system as most often associated with metabolic aging.
Hematopoietic stem cell transplantation (HSCT) has evolved for >20 years as a specific treatment of patients with autoimmune disease (AD). Using European Society for Blood and Marrow Transplantation ...registry data, we summarized trends and identified factors influencing activity and outcomes in patients with AD undergoing first autologous HSCT (n = 1951; median age, 37 years 3-76) and allogeneic HSCT (n = 105; median age, 12 years <1-62) in 247 centers in 40 countries from 1994 to 2015. Predominant countries of activity were Italy, Germany, Sweden, the United Kingdom, The Netherlands, Spain, France, and Australia. National activity correlated with the Human Development Index (P = .006). For autologous HSCT, outcomes varied significantly between diseases. There was chronological improvement in progression-free survival (PFS, P < 10−5), relapse/progression (P < 10−5), and nonrelapse mortality (P = .01). Health care expenditure was associated with improved outcomes in systemic sclerosis and multiple sclerosis (MS). On multivariate analysis selecting adults for MS, systemic sclerosis, and Crohn disease, better PFS was associated with experience (≥23 transplants for AD, P = .001), learning (time from first HSCT for AD ≥6 years, P = .01), and Joint Accreditation Committee of the International Society for Cellular Therapy and European Society for Blood and Marrow Transplantation accreditation status (P = .02). Despite improved survival over time (P = .02), allogeneic HSCT use remained low and largely restricted to pediatric practice. Autologous HSCT has evolved into a treatment modality to be considered alongside other modern therapies in severe AD. Center experience, accreditation, interspecialty networking, and national socioeconomic factors are relevant for health service delivery of HSCT in AD.
•Using EBMT data in >2000 patients from 1994 to 2015, we analyzed the development and factors influencing outcomes of HSCT for ADs.•Transplant center experience, accreditation, and national socioeconomic factors are relevant for outcomes and future health service delivery.
Natalizumab (NTZ) is a drug that has been widely used in the treatment of multiple sclerosis (MS). NTZ is very effective in suppressing inflammation, but if treatment is suspended many patients will ...experience relapses.
To investigate if quantification of γδ T cells and HLA-DR+ NK cells could predict early disease reactivation after NTZ suspension.
Absolute counts of γδ T cells and HLA-DR+ NK cells in whole blood were determined with flow cytometry in fifteen patients treated with NTZ. NTZ treatment was then withdrawn and patients were followed with clinical visits and MR investigations.
Patients with recurrent disease had higher absolute counts of γδ T cells 129 (±156) cells/μl in comparison to patients with stable disease 50.0 (±51.0) cells/μl but the difference was not statistically significant and largely driven by outliers. Patients with recurrent and stable disease had similar absolute counts of HLA-DR+ NK cells.
Quantification of γδ T cells and HLA-DR+ NK cells could not predict active disease after NTZ suspension.
PDF
