Background
Patients with multiple sclerosis (MS) receiving immunomodulatory drugs were excluded from clinical trials on COVID-19 vaccines. Therefore, data regarding the efficacy of COVID-19 vaccines ...to induce humoral immunity in MS patients treated with B- and T-cell depleting agents is urgently warranted. Cladribine tablets are a high-efficacy disease-modifying treatment that exerts its therapeutic effect via sustained but transient lymphocyte depletion.
Aim
We report humoral responses in a German cohort of MS patients treated with cladribine tablets.
Methods
This retrospective analysis included patients ≥18 years who were treated with cladribine tablets for relapsing MS in the first or second year and were fully vaccinated against COVID-19. Two weeks after the second vaccination at the earliest, blood samples were obtained for the assessment of anti-SARS-CoV-2 IgG antibodies, lymphocyte counts, B-cells, CD4+ T-cells, and CD8+ T-cells. Anti-SARS-CoV-2 IgG antibodies were quantified with the LIAISON® SARS-CoV-2 TrimericS IgG assay. Positivity was defined at a cutoff value of 33.8 BAU/mL.
Results
In total, 38 patients (73.7% female, aged 23–66 years) were included in the analysis. Ten patients (26.3%) were treatment-naïve before initiating treatment with cladribine tablets. Most patients (84.2%) received mRNA vaccines. The time between the last dose of cladribine tablets and vaccination ranged between 2 and 96 weeks. Six patients (15.8%) were vaccinated within 4 weeks of their last cladribine dose. All patients achieved positive anti-SARS-CoV-2 IgG antibody levels. Humoral immune response was independent of age, time of vaccination in relation to the last cladribine dose, lymphocyte counts as well as B- and T-cell counts.
Conclusions
Treatment with cladribine tablets did not impair humoral response to COVID-19 vaccination. Time since last cladribine dose, age, prior therapy, lymphocyte count as well as B- and T-cell counts had no effect on seropositivity of anti-SARS-CoV-2 IgG antibodies.
BACKGROUND AND PURPOSE—Ischemic stroke causes major disability as a consequence of neuronal loss and recurrent ischemic events. Biomarkers predicting tissue damage or stroke recurrence might be ...useful to guide an individualized stroke therapy. NfL (neurofilament light chain) is a promising biomarker that might be used for this purpose.
METHODS—We used individual data of patients with an acute ischemic stroke and clinical long term follow-up. Serum NfL (sNfL) was quantified within 24 hours after admission and after 1 year and compared with other biomarkers (GDF15 growth differentiation factor 15, S100, NT-proBNP N-terminal pro-B-type natriuretic peptide, ANP atrial natriuretic peptide, and FABP fatty acid–binding protein). The primary end point was functional outcome after 90 days and cerebrovascular events and death (combined cardiovascular end point) within 36 months of follow-up.
RESULTS—Two hundred eleven patients (mean age, 68.7 years; SD, ±12.6; 41.2% women) with median clinical severity on the National Institutes of Health Stroke Scale (NIHSS) score of 3 (interquartile range, 1–5) and long-term follow-up with a median of 41.8 months (interquartile range, 40.0–44.5) were prospectively included. We observed a significant correlation between sNfL and NIHSS at hospital admission (r=0.234; P<0.001). sNfL levels increased with the grade of age-related white matter changes (P<0.001) and were able to predict unfavorable clinical outcome (modified Rankin Scale score, ≥2) 90 days after stroke (odds ratio OR, 1.562; 95% CI, 1.003–2.433; P=0.048) together with NIHSS (OR, 1.303; 95% CI, 1.164–1.458; P<0.001) and age-related white matter change rating (severe; OR, 3.326; 95% CI, 1.186–9.326; P=0.022). Similarly, sNfL was valuable for the prediction of the combined cardiovascular end point (OR, 2.002; 95% CI, 1.213–3.302; P=0.007), besides NIHSS (OR, 1.110; 95% CI, 1.000–1.232; P=0.049), diabetes mellitus (OR, 2.942; 95% CI, 1.306–6.630; P=0.005), and age-related white matter change rating (severe; OR, 4.816; 95% CI, 1.206–19.229; P=0.026) after multivariate regression analysis. Kaplan-Meier analysis revealed significantly more combined cardiovascular end points (18 14.1% versus 38 45.8%, log-rank test P<0.001) during long-term follow-up in patients with elevated sNfL levels.
CONCLUSIONS—sNFL is a valuable biomarker for functional independence 90 days after ischemic stroke and predicts cardiovascular long-term outcome.
CLINICAL TRIAL REGISTRATION—URLhttp://www.isrctn.com. Unique identifierISRCTN 46104198.
Neurological immune‐mediated side effects are rare but often severe complications of immune checkpoint inhibitor (ICI) treatment. This report describes a severe case of ...nivolumab/ipilimumab‐associated glutamic acid decarboxylase 65–positive autoimmune encephalitis. It proposes neurofilament light chain levels, a biomarker indicating axonal damage, in the cerebrospinal fluid and serum as a putative novel biomarker for this diagnostically and therapeutically challenging entity with an often unfavorable outcome. Additionally, we provide an overview of previous reports of patients developing autoimmune encephalitis under ICI treatment.
Immune checkpoint inhibitor therapies are highly effective for the treatment of cancer, but are associated with rare but often severe and therapy‐limiting complications. Among the emerging spectrum of neurological immune‐mediated side effects, our report describes a case of nivolumab/ipilimumab–associated glutamic acid decarboxylase 65–positive autoimmune encephalitis. It proposes neurofilament light chain (NfL) levels, a biomarker indicating axonal damage, in the cerebrospinal fluid and serum as a putative novel biomarker for this diagnostically and therapeutically challenging entity with an often unfavorable outcome.
Background and purpose
Diagnosing small fiber neuropathies can be challenging. To address this issue, whether serum neurofilament light chain (sNfL) could serve as a potential biomarker of damage to ...epidermal Aδ‐ and C‐fibers was tested.
Methods
Serum NfL levels were assessed in 30 patients diagnosed with small fiber neuropathy and were compared to a control group of 19 healthy individuals. Electrophysiological studies, quantitative sensory testing and quantification of intraepidermal nerve fiber density after skin biopsy were performed in both the proximal and distal leg.
Results
Serum NfL levels were not increased in patients with small fiber neuropathy compared to healthy controls (9.1 ± 3.9 and 9.4 ± 3.8, p = 0.83) and did not correlate with intraepidermal nerve fiber density at the lateral calf or lateral thigh or with other parameters of small fiber impairment.
Conclusion
Serum NfL levels cannot serve as a biomarker for small fiber damage.
Background
The presence of contrast enhancement (CE) on magnetic resonance imaging (MRI) is one of the principal criteria for diagnosis and disease activity of multiple sclerosis (MS). Therefore, MS ...patients are frequently exposed to contrast agents, which may cause deposition in the brain, restricting its use in repeat examinations. Thus, serum biomarkers may be valuable as surrogate parameters to evaluate MS activity.
Methods
REDUCE‐GAD was a prospective, multicentric, biobanking study to determine whether established serum markers (neurofilament light chain NfL, glial fibrillary acidic protein GFAP, tau protein, ubiquitin‐carboxyl‐terminal‐hydrolase (UCH‐L1), S100B and matrix‐metalloproteinase 9 MMP9) are predictive of CE‐positive MRI lesions. Blood samples were obtained from patients undergoing MRI 5 days before or after collection.
Results
Patients (N = 102) from four different centers with confirmed MS or related disorders were included; n = 57 (55.9%) showed CE on MRI versus n = 45 (44.1%) without CE. Only higher NfL values indicated CE (odds ratio OR 1.05; 95% CI 1.0–1.09) and were correlated with number (ρ = 0.47; p < 0.001) and diameter of CE lesions (ρ = 0.58; p < 0.001). Nfl Z‐scores improved diagnostic accuracy (OR 1.52; 95% CI 1.06–2.18). Receiver operator characteristic analysis revealed a reasonable cut‐off value for NfL at 14.1 pg/mL (sensitivity 49.1%; specificity 82.2%; positive predictive value 77.8%; negative predictive value 56.0%). NfL ≥59.2 pg/mL was exclusively observed in patients with CE.
Conclusions
Evaluation of several possible serum biomarkers for CE in MS patients provided the most robust results for NfL, particularly as Z‐scores. Following further evaluation, biomarkers may help stratify the application of contrast agents for brain imaging in MS patients.
Objectives
To test if the early kinetics of neurofilament light (NFL) in blood adds to the absolute values of NFL in the prediction of outcome, and to evaluate if NFL can discriminate individuals ...with severe hypoxic–ischemic brain injury (sHIBI) from those with other causes of poor outcome after out-of-hospital cardiac arrest (OHCA).
Design and setting
Monocentric retrospective study involving individuals following non-traumatic OHCA between April 2014 and April 2016. NFL concentrations were determined on a SiMoA HD-1 device using NF-Light Advantage Kits.
Participants
Of 73 patients screened, 53 had serum samples available for NFL measurement at three timepoints (after 3, 24, and 48 h of admission). Of these 53 individuals, 43.4% had poor neurologic outcome at discharge as assessed by Glasgow–Pittsburgh cerebral performance categories, and, according to a current prognostication algorithm, poor outcome due to sHIBI in 20.7%.
Main outcome measure
Blood NFL and its early kinetics for prognostication of outcome and prediction of sHIBI after OHCA.
Results
An absolute NFL > 508.6 pg/ml 48 h after admission, or a change in NFL > 494 pg/ml compared with an early baseline value predicted outcome, and discriminated severe sHIBI from other causes of unfavorable outcome after OHCA with high sensitivity (100%, 95%CI 70.0–100%) and specificity (91.7%, 95%CI 62.5–100%).
Conclusions
Not only absolute values of NFL, but also early changes in NFL predict the outcome following OHCA, and may differentiate sHIBI from other causes of poor outcome after OHCA with high sensitivity and specificity. Our study adds to published data, overall corroborating that NFL measured in blood should be implemented in prognostication algorithms used in clinical routine.
IL-17-producing CD8
(Tc17) cells are enriched in active lesions of patients with multiple sclerosis (MS), suggesting a role in the pathogenesis of autoimmunity. Here we show that amelioration of MS ...by dimethyl fumarate (DMF), a mechanistically elusive drug, associates with suppression of Tc17 cells. DMF treatment results in reduced frequency of Tc17, contrary to Th17 cells, and in a decreased ratio of the regulators RORC-to-TBX21, along with a shift towards cytotoxic T lymphocyte gene expression signature in CD8
T cells from MS patients. Mechanistically, DMF potentiates the PI3K-AKT-FOXO1-T-BET pathway, thereby limiting IL-17 and RORγt expression as well as STAT5-signaling in a glutathione-dependent manner. This results in chromatin remodeling at the Il17 locus. Consequently, T-BET-deficiency in mice or inhibition of PI3K-AKT, STAT5 or reactive oxygen species prevents DMF-mediated Tc17 suppression. Overall, our data disclose a DMF-AKT-T-BET driven immune modulation and suggest putative therapy targets in MS and beyond.
Abstract
Objective
Ongoing neuroaxonal damage is a major contributor to disease progression and long-term disability in multiple sclerosis. However, spatio-temporal distribution and ...pathophysiological mechanisms of neuroaxonal damage during acute relapses and later chronic disease stages remain poorly understood.
Methods
Here, we applied immunohistochemistry, single-molecule array, spatial transcriptomics, and microglia/axon co-cultures to gain insight into spatio-temporal neuroaxonal damage in experimental autoimmune encephalomyelitis (EAE).
Results
Association of spinal cord white matter lesions and blood-based neurofilament light (sNfL) levels revealed a distinct, stage-dependent anatomical pattern of neuroaxonal damage: in chronic EAE, sNfL levels were predominately associated with anterolateral lumbar lesions, whereas in early EAE sNfL showed no correlation with lesions in any anatomical location. Furthermore, neuroaxonal damage in late EAE was largely confined to white matter lesions but showed a widespread distribution in early EAE. Following this pattern of neuroaxonal damage, spatial transcriptomics revealed a widespread cyto- and chemokine response at early disease stages, whereas late EAE was characterized by a prominent glial cell accumulation in white matter lesions. These findings were corroborated by immunohistochemistry and microglia/axon co-cultures, which further revealed a strong association between CNS myeloid cell activation and neuroaxonal damage both in vivo and in vitro.
Interpretation
Our findings indicate that CNS myeloid cells may play a crucial role in driving neuroaxonal damage in EAE. Moreover, neuroaxonal damage can progress in a stage-dependent centripetal manner, transitioning from normal-appearing white matter to focal white matter lesions. These insights may contribute to a better understanding of neurodegeneration and elevated sNfL levels observed in multiple sclerosis patients at different disease stages.
Graphical Abstract
Abstract
Objective
Intravenous methylprednisolone is the standard treatment for a multiple sclerosis relapse; however, this fails to improve symptoms in up to one quarter of patients. ...Immunoadsorption is an accepted treatment for refractory relapses, but prospective comparator-controlled studies are missing.
Methods
In this observational study, patients with steroid-refractory acute multiple sclerosis relapses receiving either six courses of tryptophan-immunoadsorption or double-dose methylprednisolone therapy were analysed. Outcomes were evaluated at discharge and three months later. Immune profiling of blood lymphocytes and proteomic analysis were performed by multi-parameter flow cytometry and Olink analysis, respectively (NCT04450030).
Results
42 patients were enrolled (methylprednisolone: 26 patients; immunoadsorption: 16 patients). For determination of the primary outcome, treatment response was stratified according to relative function system score changes (“full/best” vs. “average” vs. “worse/none”). Upon discharge, the adjusted odds ratio for any treatment response (“full/best” + ”average” vs. “worse/none”) was 10.697 favouring immunoadsorption (
p
= 0.005 compared to methylprednisolone). At follow-up, the adjusted odds ratio for the best treatment response (“full/best” vs. “average” + ”worse/none”) was 103.236 favouring IA patients (
p
= 0.001 compared to methylprednisolone). Similar results were observed regarding evoked potentials and quality of life outcomes, as well as serum neurofilament light-chain levels. Flow cytometry revealed a profound reduction of B cell subsets following immunoadsorption, which was closely correlated to clinical outcomes, whereas methylprednisolone had a minimal effect on B cell populations. Immunoadsorption treatment skewed the blood cytokine network, reduced levels of B cell-related cytokines and reduced immunoglobulin levels as well as levels of certain coagulation factors.
Interpretation
Immunoadsorption demonstrated favourable outcomes compared to double-dose methylprednisolone. Outcome differences were significant at discharge and follow-up. Further analyses identified modulation of B cell function as a potential mechanism of action for immunoadsorption, as reduction of B cell subsets correlated with clinical improvement.
Combination treatment with BRAF/MEK inhibitors favorably impact progression-free survival in malignant melanoma. However, it may cause paradoxical activation of the MAPK/ERK pathway in immune cells ...without BRAF mutation, which may lead to over activation of the immune system, especially in patients with pre-existing autoimmune conditions. In this case report, treatment of malignant melanoma with BRAF/MEK inhibitors was associated with radiological disease exacerbation of pre-existing multiple sclerosis (MS).
A 47-year-old patient with pre-existing MS was diagnosed with malignant melanoma in June 2020. Anti-tumor treatment was initiated with a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib. In February 2022, the patient presented at our neurological clinic after routine MRI revealed exacerbation of radiological MS disease activity with ten new and gadolinium-enhancing lesions, and concomitant high levels of neurofilament light chain (NfL) in serum, a marker for axonal damage. In-depth analysis of immune cells in both peripheral blood and cerebrospinal fluid was performed by multi-color flow cytometry. After treatment with the B cell-depleting antibody ocrelizumab, MS disease stability was obtained and anti-tumor medication could be continued.
Immunomodulatory treatment in cancer patients is highly effective from an oncological point of view, but may be associated with autoimmune side effects. This is of special importance in patients with pre-existing autoimmune diseases, as reflected by our case of MS disease reactivation under treatment with BRAF/MEK inhibitors. In our case, sequential modulation of immune cell subsets by B cell depletion, associated with marked shifts in B and T cell subsets, allowed for stabilization of disease and continuation of anti-tumor treatment.
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