Specific Patterns of Immune Cell Dynamics May Explain the Early Onset and Prolonged Efficacy of Cladribine Tablets: A MAGNIFY-MS Substudy

Cladribina; Cèl·lules immunitàriesCladribina; Células inmunitariasCladribine; Immune cellsBackground and Objectives Cladribine tablets cause a reduction in lymphocytes with a predominant effect on B-cell and T-cell counts. The MAGNIFY-MS substudy reports the dynamic changes on multiple peripheral blood mononuclear cell (PBMC) subtypes and immunoglobulin (Ig) levels over 12 months after the first course of cladribine tablets in patients with highly active relapsing multiple sclerosis (MS). Methods Immunophenotyping was performed at baseline (predose) and at the end of months 1, 2, 3, 6, and 12 after initiating treatment with cladribine tablets. Assessments included lymphocyte subtype counts of CD19+ B cells, CD4+ and CD8+ T cells, CD16+ natural killer cells, plasmablasts, and Igs. Immune cell subtypes were analyzed by flow cytometry, and serum IgG and IgM were analyzed by nephelometric assay. Absolute cell counts and percentage change from baseline were assessed. Results The full analysis set included 57 patients. Rapid reductions in median CD19+, CD20+, memory, activated, and naive B-cell counts were detected, reaching nadir by month 2. Thereafter, total CD19+, CD20+, and naive B-cell counts subsequently reconstituted, but memory B cells remained reduced by 93%–87% for the remainder of the study. The decrease in plasmablasts was slower, reaching nadir at month 3. Decrease in T-cell subtypes was also slower and more moderate compared with B-cell subtypes, reaching nadir between months 3 and 6. IgG and IgM levels remained within the normal range over the 12-month study period. Discussion Cladribine tablets induce a specific pattern of early and sustained PBMC subtype dynamics in the absence of relevant Ig changes: While total B cells were reduced dramatically, T cells were affected significantly less. Naive B cells recovered toward baseline, naive CD4 and CD8 T cells did not, and memory B cells remained reduced. The results help to explain the unique immune depletion and repopulation architecture regarding onset of action and durability of effects of cladribine tablets while largely maintaining immune competence.This work was supported by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945)

Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis: APLIOS, a randomized phase-2 study

Ofatumumab; Multiple sclerosis; PharmacokineticsOfatumumab; Esclerosis múltiple; FarmacocinéticaOfatumumab; Esclerosi múltiple; FarmacocinèticaBackground: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS). Objective: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion. Methods: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUCτ) and maximum plasma concentration (Cmax) for Weeks 8–12. B-cell depletion and safety/tolerability were assessed. Results: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUCτ, 487.7 vs 474.1 h × µg/mL (ratio 1.03); Cmax, 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated. Conclusion: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the APLIOS trial was funded by Novartis Pharmaceuticals. Novartis Pharmaceuticals supported the development of this manuscript, provided data analyses according to the direction of the authors, and paid for medical writing support

Clinical effects of natalizumab on multiple sclerosis appear early in treatment course

In clinical practice natalizumab is typically used in patients who have experienced breakthrough disease during treatment with interferon beta (IFNβ) or glatiramer acetate. In these patients it is important to reduce disease activity as quickly as possible. In a phase II study, differences between natalizumab and placebo in MRI outcomes reflecting inflammatory activity were evident after the first infusion and maintained through a 6-month period, suggesting a rapid onset of natalizumab treatment effects. To explore how soon after natalizumab initiation clinical effects become apparent, annualized relapse rates per 3-month period and time to first relapse were analyzed in the phase III AFFIRM study (natalizumab vs. placebo) and in the multinational Tysabri® Observational Program (TOP). In AFFIRM, natalizumab reduced the annualized relapse rate within 3months of treatment initiation compared with placebo in the overall population (0.30 vs. 0.71; p<0.0001) and in patients with highly active disease (0.30 vs. 0.94; p=0.0039). The low annualized relapse rate was maintained throughout the 2-year study period, and the risk of relapse in AFFIRM patients treated with natalizumab was reduced [hazard ratio against placebo 0.42 (95% CI 0.34-0.52); p<0.0001]. Rapid reductions in annualized relapse rate also occurred in TOP (baseline 1.99 vs. 0-3months 0.26; p<0.0001). Natalizumab resulted in rapid, sustained reductions in disease activity in both AFFIRM and in clinical practice. This decrease in disease activity occurred within the first 3months of treatment even in patients with more active diseas

Two pore domain potassium channels in cerebral ischemia: a focus on K2P9.1 (TASK3, KCNK9)

BACKGROUND: Recently, members of the two-pore domain potassium channel family (K2P channels) could be shown to be involved in mechanisms contributing to neuronal damage after cerebral ischemia. K2P3.1-/- animals showed larger infarct volumes and a worse functional outcome following experimentally induced ischemic stroke. Here, we question the role of the closely related K2P channel K2P9.1. METHODS: We combine electrophysiological recordings in brain-slice preparations of wildtype and K2P9.1-/- mice with an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of K2P9.1 in stroke formation. RESULTS: Patch-clamp recordings reveal that currents mediated through K2P9.1 can be obtained in slice preparations of the dorsal lateral geniculate nucleus (dLGN) as a model of central nervous relay neurons. Current characteristics are indicative of K2P9.1 as they display an increase upon removal of extracellular divalent cations, an outward rectification and a reversal potential close to the potassium equilibrium potential. Lowering extracellular pH values from 7.35 to 6.0 showed comparable current reductions in neurons from wildtype and K2P9.1-/- mice (68.31 +/- 9.80% and 69.92 +/- 11.65%, respectively). These results could be translated in an in vivo model of cerebral ischemia where infarct volumes and functional outcomes showed a none significant tendency towards smaller infarct volumes in K2P9.1-/- animals compared to wildtype mice 24 hours after 60 min of tMCAO induction (60.50 +/- 17.31 mm3 and 47.10 +/- 19.26 mm3, respectively). CONCLUSIONS: Together with findings from earlier studies on K2P2.1-/- and K2P3.1-/- mice, the results of the present study on K2P9.1-/- mice indicate a differential contribution of K2P channel subtypes to the diverse and complex in vivo effects in rodent models of cerebral ischemia

Increased cortical curvature reflects white matter atrophy in individual patients with early multiple sclerosis

AbstractObjectiveWhite matter atrophy occurs independently of lesions in multiple sclerosis. In contrast to lesion detection, the quantitative assessment of white matter atrophy in individual patients has been regarded as a major challenge. We therefore tested the hypothesis that white matter atrophy (WMA) is present at the very beginning of multiple sclerosis (MS) and in virtually each individual patient. To find a new sensitive and robust marker for WMA we investigated the relationship between cortical surface area, white matter volume (WMV), and whole-brain-surface-averaged rectified cortical extrinsic curvature. Based on geometrical considerations we hypothesized that cortical curvature increases if WMV decreases and the cortical surface area remains constant.MethodsIn total, 95 participants were enrolled: 30 patients with early and advanced relapsing–remitting MS; 30 age-matched control subjects; 30 patients with Alzheimer's disease (AD) and 5 patients with clinically isolated syndrome (CIS).Results29/30 MS and 5/5 CIS patients showed lower WMV than expected from their intracranial volume (average reduction 13.0%, P<10−10), while the cortical surface area showed no significant differences compared with controls. The estimated WMV reductions were correlated with an increase in cortical curvature (R=0.62, P=0.000001). Discriminant analysis revealed that the curvature increase was highly specific for the MS and CIS groups (96.7% correct assignments between MS and control groups) and was significantly correlated with reduction of white matter fractional anisotropy, as determined by diffusion tensor imaging and the Expanded Disability Status Scale. As expected by the predominant gray and WM degeneration in AD, no systematic curvature increase was observed in AD.ConclusionWhole-brain-averaged cortical extrinsic curvature appears to be a specific and quantitative marker for a WMV–cortex disproportionality and allows us to assess “pure” WMA without being confounded by intracranial volume. WMA seems to be a characteristic symptom in early MS and can already occur in patients with CIS and should thus be considered in future MS research and clinical studies

Impaired Autonomic Responses to Emotional Stimuli in Autoimmune Limbic Encephalitis

Limbic encephalitis (LE) is an autoimmune-mediated disorder that affects structures of the limbic system, in particular the amygdala. The amygdala constitutes a brain area substantial for processing of emotional, especially fear-related signals. The amygdala is also involved in neuroendocrine and autonomic functions, including skin conductance responses (SCRs) to emotionally arousing stimuli. This study investigates behavioral and autonomic responses to discrete emotion-evoking and neutral film clips in a patient suffering from LE associated with contactin-associated protein-2 (CASPR2)-antibodies as compared to a healthy control group. Results show a lack of SCRs in the patient while watching the film clips, with significant differences compared to healthy controls in the case of fear-inducing videos. There was no comparable impairment in behavioral data (emotion report, valence and arousal ratings). The results point to a defective modulation of sympathetic responses during emotional stimulation in patients with LE, probably due to impaired functioning of the amygdala