Fast but not furious: Rapid ocrelizumab infusion as a strategy to optimize multiple sclerosis patients' management.

OBJECTIVES: Multiple sclerosis clinicians are continuously challenged to be innovative in delivering therapies and there is ongoing pressure to maximize day-hospital vacancies. We describe our single-center experience with ocrelizumab (OCR) rapid infusion (OCR-RI) in patients with MS (pwMS). METHODS: For pwMS with prior exposure to OCR standard infusion (OCR-SI) for at least one year/two cycles, infusion time was reduced from 3.5 to 2.0 h. A comparative analysis between OCR-RI vs OCR-SI patients was conducted. RESULTS: 283 (76.7%) out of 369 OCR-treated pwMS performed OCR-RI; 86 subjects did not start OCR-RI due to infusion-related reactions (IRR) occurring with OCR-SI (n = 13) or OCR-treatment duration shorter than one year (n = 73). Disease duration was longer in OCR-RI (p < 0.001). Median numbers of overall-OCR and OCR-RI cycles were 7 (IQR = 5-8) and 4 (IQR = 2-5) (p < 0.001). Overall, 38 (10.3%) IRR were reported, 25 (8.8%) in OCR-RI and 13 (15.1%) in OCR-SI group. IRR frequency did not differ between the two groups (p = 0.106). IRR included throat irritation, rash, hypotension, fever and gastrointestinal symptoms. IRR severity was mild (81.6%) or moderate (18.4%), all resolved and did not differ in distribution between the two groups. When IRR occurred, infusions were temporarily stopped, hydration and/or symptomatic medications were given and infusions were subsequently resumed at standard velocity. OCR-RI was not a risk factor for IRR (OR 0.55, 95% CI: 0.27-1.13, p = 0.096). CONCLUSIONS: In our cohort, IRR frequency, severity and management were comparable to literature. No severe IRR were observed. RI protocols represent a strategy to optimize patients' management in the clinic.

Age-induced alterations of granulopoiesis generate atypical neutrophils that aggravate stroke pathology.

Aging accounts for increased risk and dismal outcome of ischemic stroke. Here, we investigated the impact of age-related changes in the immune system on stroke. Upon experimental stroke, compared with young mice, aged mice had increased neutrophil clogging of the ischemic brain microcirculation, leading to worse no-reflow and outcomes. Aged mice showed an enhanced granulopoietic response to stroke that led to the accumulation of CD101+CD62Llo mature and CD177hiCD101loCD62Llo and CD177loCD101loCD62Lhi immature atypical neutrophils in the blood, endowed with increased oxidative stress, phagocytosis and procoagulant features. Production of CXCL3 by CD62Llo neutrophils of the aged had a key role in the development and pathogenicity of aging-associated neutrophils. Hematopoietic stem cell rejuvenation reverted aging-associated neutropoiesis and improved stroke outcome. In elderly patients with ischemic stroke, single-cell proteome profile of blood leukocytes identified CD62Llo neutrophil subsets associated with worse reperfusion and outcome. Our results unveil how stroke in aging leads to a dysregulated emergency granulopoiesis impacting neurological outcome.

Ocrelizumab extended-interval dosing in multiple sclerosis during SARS-CoV-2 pandemic: a real-world experience.

BACKGROUND AND PURPOSE: During the COVID-19 pandemic, ocrelizumab administration was frequently postponed because of a lack of safety information and to favour vaccination. The clinical implications of ocrelizumab administration delay in multiple sclerosis (MS) patients were assessed. METHODS: Relapsing (RMS) and primary progressive (PPMS) MS patients receiving ocrelizumab for at least 6 months at our centre were retrospectively classified, according to the possible occurrence of a delay (≥4 weeks) in treatment administration. Patients were categorized in the extended-interval dosing (EID) group in the presence of at least one delayed infusion; otherwise they were considered as part of the standard interval dosing (SID) cohort. MS history, magnetic resonance imaging examinations and B-cell counts were also retrospectively collected and analysed. RESULTS: A total of 213 RMS and 61 PPMS patients were enrolled; 115 RMS and 29 PPMS patients had been treated according to the SID regimen, whilst 98 RMS and 32 PPMS patients were included in the EID cohort. Average follow-up after delay was 1.28 ± 0.7 years in the EID cohort. In RMS, comparing SID and EID patients, no differences were found considering the occurrence of clinical relapses (9.6% vs. 16.3%, p = 0.338), magnetic resonance imaging activity (9.8% vs. 14.1%, p = 0.374) or disability progression (11.3% vs. 18.4%, p = 0.103). Similar findings were observed in PPMS patients. In the pooled EID group, treatment delay correlated with CD19-positive relative (r = 0.530, p < 0.001) and absolute (r = 0.491, p < 0.001) cell counts, without implications on disease activity. CONCLUSIONS: Sporadic ocrelizumab administration delay granted sustained treatment efficacy in our cohort. Prospective data should be obtained to confirm these observations and set up systematic extended-interval regimens.

Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study.

Innovative pro-regenerative treatment strategies for progressive multiple sclerosis (PMS), combining neuroprotection and immunomodulation, represent an unmet need. Neural precursor cells (NPCs) transplanted in animal models of multiple sclerosis have shown preclinical efficacy by promoting neuroprotection and remyelination by releasing molecules sustaining trophic support and neural plasticity. Here we present the results of STEMS, a prospective, therapeutic exploratory, non-randomized, open-label, single-dose-finding phase 1 clinical trial ( NCT03269071 , EudraCT 2016-002020-86), performed at San Raffaele Hospital in Milan, Italy, evaluating the feasibility, safety and tolerability of intrathecally transplanted human fetal NPCs (hfNPCs) in 12 patients with PMS (with evidence of disease progression, Expanded Disability Status Scale ≥6.5, age 18-55 years, disease duration 2-20 years, without any alternative approved therapy). The safety primary outcome was reached, with no severe adverse reactions related to hfNPCs at 2-year follow-up, clearly demonstrating that hfNPC therapy in PMS is feasible, safe and tolerable. Exploratory secondary analyses showed a lower rate of brain atrophy in patients receiving the highest dosage of hfNPCs and increased cerebrospinal fluid levels of anti-inflammatory and neuroprotective molecules. Although preliminary, these results support the rationale and value of future clinical studies with the highest dose of hfNPCs in a larger cohort of patients.

Promoting exogenous repair in multiple sclerosis: myelin regeneration.

PURPOSE OF THE REVIEW: Despite the significant progress in the development of disease-modifying treatments for multiple sclerosis (MS), repair of existing damage is still poorly addressed. Current research focuses on stem cell-based therapies as a suitable alternative or complement to current drug therapies. RECENT FINDINGS: Myelin damage is a hallmark of multiple sclerosis, and novel approaches leading to remyelination represent a promising tool to prevent neurodegeneration of the underlying axon. With increasing evidence of diminishing remyelination capacity of the MS brain with ageing and disease progression, exogenous cell transplantation is a promising therapeutic approach for restoration of oligodendrocyte precursor cell pool reserve and myelin regeneration. SUMMARY: The present review summarizes recent developments of remyelinating therapies in multiple sclerosis, focusing on exogenous cell-based strategies and discussing related scientific, practical, and ethical concerns.

Neutrophils predominate the immune signature of cerebral thrombi in COVID-19 stroke patients.

Coronavirus disease 2019 (COVID-19) is associated with an increased risk of thrombotic events. Ischemic stroke in COVID-19 patients entails high severity and mortality rates. Here we aimed to analyze cerebral thrombi of COVID-19 patients with large vessel occlusion (LVO) acute ischemic stroke to expose molecular evidence for SARS-CoV-2 in the thrombus and to unravel any peculiar immune-thrombotic features. We conducted a systematic pathological analysis of cerebral thrombi retrieved by endovascular thrombectomy in patients with LVO stroke infected with COVID-19 (n = 7 patients) and non-covid LVO controls (n = 23). In thrombi of COVID-19 patients, the SARS-CoV-2 docking receptor ACE2 was mainly expressed in monocytes/macrophages and showed higher expression levels compared to controls. Using polymerase chain reaction and sequencing, we detected SARS-CoV-2 Clade20A, in the thrombus of one COVID-19 patient. Comparing thrombus composition of COVID-19 and control patients, we noted no overt differences in terms of red blood cells, fibrin, neutrophil extracellular traps (NETs), von Willebrand Factor (vWF), platelets and complement complex C5b-9. However, thrombi of COVID-19 patients showed increased neutrophil density (MPO+ cells) and a three-fold higher Neutrophil-to-Lymphocyte Ratio (tNLR). In the ROC analysis both neutrophils and tNLR had a good discriminative ability to differentiate thrombi of COVID-19 patients from controls. In summary, cerebral thrombi of COVID-19 patients can harbor SARS-CoV2 and are characterized by an increased neutrophil number and tNLR and higher ACE2 expression. These findings suggest neutrophils as the possible culprit in COVID-19-related thrombosis.

Cerebral thrombi of cardioembolic etiology have an increased content of neutrophil extracellular traps.

BACKGROUND: Inflammation is emerging as an essential trigger for thrombosis. In the interplay between innate immunity and coagulation cascade, neutrophils and neutrophil extracellular traps (NETs) can promote thrombus formation and stabilization. In ischemic stroke, it is uncertain whether the involvement of the inflammatory component may differ in thrombi of diverse etiology. We here aimed to evaluate the presence of neutrophils and NETs in cerebral thrombi of diverse etiology retrieved by endovascular thrombectomy (EVT). METHODS: We performed a systematic histological analysis on 80 human cerebral thrombi retrieved through EVT in acute ischemic stroke patients. Thrombus composition was investigated in terms of neutrophils (MPO+ cells) and NET content (citH3+ area), employing specific immunostainings. NET plasma content was determined and compared to NET density in the thrombus. RESULTS: Neutrophils and NETs were heterogeneously represented within all cerebral thrombi. Thrombi of diverse etiology did not display a statistically significant difference in the number of neutrophils (p = 0.51). However, NET content was significantly increased in cardioembolic compared to large artery atherosclerosis thrombi (p = 0.04), and the association between NET content and stroke etiology remained significant after adjusted analysis (beta coefficient = -6.19, 95%CI = -11.69 to -1.34, p = 0.01). Moreover, NET content in the thrombus was found to correlate with NET content in the plasma (p ≤ 0.001, r = 0.62). CONCLUSION: Our study highlights how the analysis of the immune component within the cerebral thrombus, and specifically the NET burden, might provide additional insight for differentiating stroke from diverse etiologies.

Immune Reconstitution Following Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis: A Review on Behalf of the EBMT Autoimmune Diseases Working Party.

Multiple sclerosis (MS) is a central nervous system (CNS) disorder, which is mediated by an abnormal immune response coordinated by T and B cells resulting in areas of inflammation, demyelination, and axonal loss. Disease-modifying treatments (DMTs) are available to dampen the inflammatory aggression but are ineffective in many patients. Autologous hematopoietic stem cell transplantation (HSCT) has been used as treatment in patients with a highly active disease, achieving a long-term clinical remission in most. The rationale of the intervention is to eradicate inflammatory autoreactive cells with lympho-ablative regimens and restore immune tolerance. Immunological studies have demonstrated that autologous HSCT induces a renewal of TCR repertoires, resurgence of immune regulatory cells, and depletion of proinflammatory T cell subsets, suggesting a "resetting" of immunological memory. Although our understanding of the clinical and immunological effects of autologous HSCT has progressed, further work is required to characterize the mechanisms that underlie treatment efficacy. Considering that memory B cells are disease-promoting and stem-like T cells are multipotent progenitors involved in self-regeneration of central and effector memory cells, investigating the reconstitution of B cell compartment and stem and effector subsets of immunological memory following autologous HSCT could elucidate those mechanisms. Since all subjects need to be optimally protected from vaccine-preventable diseases (including COVID-19), there is a need to ensure that vaccination in subjects undergoing HSCT is effective and safe. Additionally, the study of vaccination in HSCT-treated subjects as a means of evaluating immune responses could further distinguish broad immunosuppression from immune resetting.

Refractory anti-NMDAR encephalitis successfully treated with bortezomib and associated movements disorders controlled with tramadol: a case report with literature review.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a potentially fatal autoimmune disease, characterized by autoantibody-mediated neurotransmission impairment in multiple brain locations. The course of this condition often comprises altered mental status, autonomic dysfunctions, refractory seizures and hyperkinetic movement disorders. Available disease-modifying therapies include corticosteroids, i.v. immunoglobulins, plasma exchange, rituximab and cyclophosphamide. In a subgroup of patients not responding to B-cell depletion, bortezomib, a proteasome inhibitor, has shown promising evidence of efficacy. The time course of recovery from acute phase may be very slow (weeks/months), and only few data are available in literature about the concurrent management of encephalitis-associated movement disorders. We report a case of severe anti-NMDAR encephalitis in a 29-year-old woman, not responsive to first- and second-line treatments, with persistent involuntary motor manifestations. Starting three months after symptom onset, four cycles of bortezomib have been administered; subsequently we observed a progressive improvement of neurological status. Meanwhile, motor manifestations were controlled after the administration of tramadol, a non-competitive NMDA receptor antagonist.