Non-inferiority analysis of subcutaneous versus intravenous 300 mg monthly natalizumab administration: A post hoc analysis of the REFINE study.

To quantify the probability that monthly intravenous (IV) and subcutaneous (SC) natalizumab (NTZ) had similar efficacy in relapsing-remitting multiple sclerosis (RRMS), non-inferiority of efficacy of NTZ-SC versus NTZ-IV on combined MRI unique active lesions number (CUAL) was explored re-analysing the REFINE data set. Non-inferiority margins were selected equal to 25%/33%/50% fractions of the effect size of NTZ-IV versus placebo observed in the AFFIRM study. Ninety-nine RRMS were included. NTZ-SC resulted not inferior to NTZ-IV on CUAL for all margins at 2.5% significance level, and, in worst-case scenario, its effect over NTZ-IV did not exceed 3.5% (or 2.8%) of the effect of NTZ-IV versus placebo.

Successful switch to ofatumumab after liver injury associated with ocrelizumab treatment in multiple sclerosis: a case report.

Drug-induced liver injury (DILI) is a potential adverse event of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS), as well as of methylprednisolone pulsed therapy used in case of MS relapse. DILI may be induced by different mechanisms, including idiosyncratic reaction, autoimmune hepatitis or viral reactivation. In patients receiving the humanized anti-CD20 monoclonal antibody (mAb) ocrelizumab, DILI has been rarely reported and was mostly associated with hepatitis B virus (HBV) reactivation. Here we present the case of a woman with highly active relapsing-remitting MS who had experienced two episodes of DILI while receiving different DMTs, and was successfully switched to ofatumumab, a fully human anti-CD20 mAb, after a further event associated with ocrelizumab treatment and unrelated to HBV reactivation. Despite sharing the mechanism of action, differences in structure, pharmacokinetic/pharmacodynamic profile, and use of ancillary drugs (only needed for ocrelizumab) may have accounted for the successful switch. To our knowledge, this is the first report of a successful switch from ocrelizumab to ofatumumab due to DILI. Ofatumumab may therefore represent a valid therapeutic option for patients experiencing DMTs- and ocrelizumab-induced liver injury, providing that HBV reactivation has been ruled out.

Disease Modifying Strategies in Multiple Sclerosis: New Rays of Hope to Combat Disability?

Multiple sclerosis (MS) is the most prevalent chronic autoimmune inflammatory- demyelinating disorder of the central nervous system (CNS). It usually begins in young adulthood, mainly between the second and fourth decades of life. Usually, the clinical course is characterized by the involvement of multiple CNS functional systems and by different, often overlapping phenotypes. In the last decades, remarkable results have been achieved in the treatment of MS, particularly in the relapsing- remitting (RRMS) form, thus improving the long-term outcome for many patients. As deeper knowledge of MS pathogenesis and respective molecular targets keeps growing, nowadays, several lines of disease-modifying treatments (DMT) are available, an impressive change compared to the relative poverty of options available in the past. Current MS management by DMTs is aimed at reducing relapse frequency, ameliorating symptoms, and preventing clinical disability and progression. Notwithstanding the relevant increase in pharmacological options for the management of RRMS, research is now increasingly pointing to identify new molecules with high efficacy, particularly in progressive forms. Hence, future efforts should be concentrated on achieving a more extensive, if not exhaustive, understanding of the pathogenetic mechanisms underlying this phase of the disease in order to characterize novel molecules for therapeutic intervention. The purpose of this review is to provide a compact overview of the numerous currently approved treatments and future innovative approaches, including neuroprotective treatments as anti-LINGO-1 monoclonal antibody and cell therapies, for effective and safe management of MS, potentially leading to a cure for this disease.

Cost and effectiveness of autologous haematopoietic stem cell transplantation and high-efficacy disease-modifying therapies in relapsing-remitting multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is a highly effective one-off treatment for relapsing-remitting multiple sclerosis (RR-MS), potentially representing an optimal front-loading strategy for costs. OBJECTIVE: Exploring cost/effectiveness of AHSCT and high-efficacy disease-modifying treatments (HE-DMTs) in RR-MS, estimating costs at our centre in Italy, where National Health Service (NHS) provides universal health coverage. METHODS: Costs (including drugs, inpatient/outpatient management) for treatment with AHSCT and HE-DMTs were calculated as NHS expenditures over 2- and 5-year periods. Cost-effectiveness for each treatment was estimated as "cost needed to treat" (CNT), i.e. expense to prevent relapses, progression, or disease activity (NEDA) in one patient over n-years, retrieving outcomes from published studies. RESULTS: Costs of AHSCT and HE-DMTs were similar over 2 years, whereas AHSCT was cheaper than most HE-DMTs over 5 years (€46 600 vs €93 800, respectively). When estimating cost-effectiveness of treatments, over 2 years, mean CNT of HE-DMTs for NEDA was twofold that of AHSCT, whereas it was similar for relapses and disability. Differences in CNT were remarkable over 5 years, especially for NEDA, being mean CNT of HE-DMTs €382 800 vs €74 900 for AHSCT. CONCLUSIONS: AHSCT may be highly cost-effective in selected aggressive RR-MS. Besides priceless benefits for treated individuals, cost-savings generated by AHSCT may contribute to improving healthcare assistance at a population level.

Case report: 3D intracranial vessel wall MRI in Susac syndrome: potential relevance for diagnosis and therapeutic management.

Background: Susac syndrome (SS) is a rare immune-mediated vasculitis affecting retina, inner ear and brain. Assessment of central nervous system (CNS) involvement is currently based on standard brain magnetic resonance imaging (MRI) sequences. Accuracy of three dimensional (3D)-vessel wall imaging (VWI) was compared to standard sequences and contrast-enhanced-3D T2-fluid attenuated inversion recovery (CE-FLAIR) to assess CNS disease activity in two cases of definite SS. Methods: Brain MRI scan and retinal fluorescein angiogram (RFA) were performed at disease onset and at 1, 3, and 6 months after induction therapy start. CE-FLAIR and VWI based on 3D black-blood proton density weighted (PDW) with and without gadolinium were added to standard sequences on a 3 Tesla MRI scanner. Results: Contrast enhanced-VWI (CE-VWI) detected an abnormal diffuse leptomeningeal enhancement (LME) in both cases at onset and during follow-up. Pathological enhancement on CE-VWI persisted at 6-month brain MRI, despite absence of new lesions and disappearance of LME on CE-FLAIR. Follow-up RFA revealed new arterial wall hyperfluorescence in both cases. Conclusions: VWI may represent a useful tool for diagnosing and monitoring CNS disease activity in SS patients, as confirmed by concordance with RFA, leading treatment's choice and timing. Moreover, CE-VWI seemed at least as sensitive as CE-FLAIR in detecting LME, possibly being superior to the latter in posterior fossa. LME remission might be not accurate in predicting suppression of CNS inflammation in SS.

Incidence and Long-term Functional Outcome of Neurologic Disorders in Hospitalized Patients With COVID-19 Infected With Pre-Omicron Variants.

BACKGROUND AND OBJECTIVES: A variety of neurologic disorders have been reported as presentations or complications of coronavirus disease 2019 (COVID-19) infection. The objective of this study was to determine their incidence dynamics and long-term functional outcome. METHODS: The Neuro-COVID Italy study was a multicenter, observational, cohort study with ambispective recruitment and prospective follow-up. Consecutive hospitalized patients presenting new neurologic disorders associated with COVID-19 infection (neuro-COVID), independently from respiratory severity, were systematically screened and actively recruited by neurology specialists in 38 centers in Italy and the Republic of San Marino. The primary outcomes were incidence of neuro-COVID cases during the first 70 weeks of the pandemic (March 2020-June 2021) and long-term functional outcome at 6 months, categorized as full recovery, mild symptoms, disabling symptoms, or death. RESULTS: Among 52,759 hospitalized patients with COVID-19, 1,865 patients presenting 2,881 new neurologic disorders associated with COVID-19 infection (neuro-COVID) were recruited. The incidence of neuro-COVID cases significantly declined over time, comparing the first 3 pandemic waves (8.4%, 95% CI 7.9-8.9; 5.0%, 95% CI 4.7-5.3; 3.3%, 95% CI 3.0-3.6, respectively; p = 0.027). The most frequent neurologic disorders were acute encephalopathy (25.2%), hyposmia-hypogeusia (20.2%), acute ischemic stroke (18.4%), and cognitive impairment (13.7%). The onset of neurologic disorders was more common in the prodromic phase (44.3%) or during the acute respiratory illness (40.9%), except for cognitive impairment whose onset prevailed during recovery (48.4%). A good functional outcome was achieved by most patients with neuro-COVID (64.6%) during follow-up (median 6.7 months), and the proportion of good outcome increased throughout the study period (r = 0.29, 95% CI 0.05-0.50; p = 0.019). Mild residual symptoms were frequently reported (28.1%) while disabling symptoms were common only in stroke survivors (47.6%). DISCUSSION: Incidence of COVID-associated neurologic disorders decreased during the prevaccination phase of the pandemic. Long-term functional outcome was favorable in most neuro-COVID disorders, although mild symptoms commonly lasted more than 6 months after infection.

Effect of the COVID-19 pandemic on disease activity in multiple sclerosis patients treated with hematopoietic stem cell transplantation.

BACKGROUND AND PURPOSE: It is still debated whether the COVID-19 pandemic affected disease activity in people with autoimmune diseases, including multiple sclerosis (MS). The aim of this study, therefore, was to explore the impact of COVID-19 in people with MS (pwMS) not receiving continuative disease-modifying therapy (DMT) after previous treatment with autologous hematopoietic stem cell transplantation (AHSCT). MATERIALS AND METHODS: We included pwMS treated with AHSCT who were in disease remission without receiving DMTs during the pandemic and who were followed up at our centre during the study period. Data on SARS-CoV-2 infection and vaccination were recorded, with details of adverse events and clinical-radiological disease activity. RESULTS: A total of 36 pwMS (31 females; 86%) were included, of whom 23 (64%) had relapsing-remitting (RR-MS) and 13 had secondary progressive MS (SP-MS). Thirty-three pwMS (92%) received anti-SARS-CoV-2 mRNA vaccines. Thirteen patients (36%) developed mild to moderate COVID-19 a median (range) of 58 (4-224) months after AHSCT; seven (54%) of these patients were not yet vaccinated. Transient neurological symptoms after vaccination or infection were reported in 9% and 36% of the patients, respectively. The rate of new inflammatory events (relapses or asymptomatic magnetic resonance imaging [MRI] activity) after AHSCT increased from 0.006 (one asymptomatic new lesion/159 patient-years) before the pandemic to 0.083 (five relapses plus two cases of asymptomatic MRI activity/84 patient-years) since the pandemic start (p = 0.004). CONCLUSIONS: People with MS with a history of highly active disease, who are untreated or receiving moderate-efficacy DMTs might be more vulnerable to disease reactivation, possibly elicited by exogenous triggers. Careful monitoring and further investigation are warranted to ascertain whether special precautions are needed in these cases.

Neurological outcomes in immune checkpoint inhibitor-related neurotoxicity.

While the spectrum of neurological immune checkpoint inhibitor-related adverse events is expanding, patients' outcomes are not well documented. This study aimed to assess outcomes of neurological immune-related adverse events and to identify prognostic factors. All patients experiencing grade ≥2 neurological immune-related adverse events identified at two clinical networks (French Reference Center for Paraneoplastic Neurological Syndromes, Lyon; and OncoNeuroTox, Paris) over five years were included. Modified Rankin scores were assessed at onset, 6, 12, 18 months, and last visit. A multi-state Markov model was used to estimate the transition rates between minor disability (mRS <3), severe disability (mRS 3-5), and death (mRS 6), over the study period. The state-to-state transition rates were estimated using maximum likelihood and variables were introduced into the different transitions to study their effects. A total of 147 patients were included out of 205 patients with a suspicion of neurological immune-related adverse events. The median age was 65 years (range 20-87) and 87/147 patients (59.2%) were male. Neurological immune-related adverse events involved the peripheral nervous system in 87/147 patients (59.2%), the central nervous system in 51/147 (34.7%), and both systems in 9/147 (6.1%). Paraneoplastic-like syndromes were observed in 30/147 patients (20.4%). Cancers included lung cancers (36.1%), melanoma (30.6%), urological cancers (15.6%), and others (17.8%). Patients were treated with programmed cell death protein (ligan) 1 (PD(L)1) inhibitors (70.1%), CTLA4 inhibitors (3.4%) or both (25.9%). Severe disability was reported in 108/144 patients (75.0%) at onset and in 33/146 patients (22.6%) at last visit (median follow-up duration: 12 months, range 0.5-50); 48/147 (32.7%) patients died, from cancer progression (17/48, 35.4%), neurological toxicity (15/48, 31.2%), other causes (10/48, 20.8%) or unknown causes (6/48, 12.5%). The rate of transition from severe to minor disability independently increased with melanoma [compared to lung cancer, hazard ratio = 3.26, 95%CI (1.27; 8.41)] and myositis/neuromuscular junction disorders [hazard ratio = 8.26, 95%CI (2.90; 23.58)], and decreased with older age [hazard ratio = 0.68, 95%CI (0.47; 0.99)] and paraneoplastic-like syndromes [hazard ratio = 0.29, 95%CI (0.09; 0.98)]. In patients with neurological immune-related adverse events, myositis/neuromuscular junction disorders and melanoma increase the transition rate from severe to minor disability, while older age and paraneoplastic-like syndromes result in poorer neurological outcomes; future studies are needed to optimize the management of such patients.

Safety and effectiveness of the booster dose of mRNA COVID-19 vaccines in people with multiple sclerosis: A monocentric experience.

BACKGROUND: Long-term data on the effectiveness and safety of the booster dose of anti-SARS-CoV-2 vaccines in people affected by multiple sclerosis (pwMS) are lacking, hence a retrospective monocentric study exploring these issues was undertaken. MATERIALS AND METHODS: PwMS who had received the booster dose of anti-COVID19 mRNA vaccines (either Comirnaty or Spikevax) according to the national regulation were included. The occurrence of adverse events or disease reactivation and SARS-CoV-2 infection were recorded up to last follow-up. Factors predictive of COVID-19 were explored using logistic regression analyses. A two-tailed p-value <0.05 was considered significant. RESULTS: One hundred and fourteen pwMS were included: 80 females (70%); median age at the booster dose 42 years (range 21 - 73); 106/114 patients (93%) were receiving a disease-modifying treatment at vaccination. The median follow-up after the booster dose was 6 (range 2 - 7) months. Adverse events were experienced in 58% of the patients, being mild to moderate in most cases; 4 reactivations of MS were observed, two of which occurring within 4 weeks after the booster. SARS-CoV-2 infection was reported in 24/114 (21%) cases, occurring a median of 74 days (5-162) after the booster dose and requiring hospitalisation in 2 patients. Six cases received direct antiviral drugs. Age at vaccination and time between the primary vaccination cycle and the booster dose were independently and inversely associated with the risk of COVID-19 (HR 0.95 and 0.98, respectively). CONCLUSIONS: The administration of the booster dose in pwMS showed an overall good safety profile and protected 79% of the patients from SARS-CoV-2 infection. The observed association between the risk of infection after the booster dose and both younger age at vaccination and shorter interval period to the booster dose suggest that unobserved confounders, possibly including behavioural and social factors, play a relevant role in determining the individual propensity to get infected with COVID-19.

Hematopoietic Stem Cell Transplantation for the Treatment of Autoimmune Neurological Diseases: An Update.

Over the last two decades, haematopoietic stem cell transplantation (HSCT) has been explored as a potential therapeutic strategy for autoimmune diseases refractory to conventional treatments, including neurological disorders. Although both autologous (AHSCT) and allogeneic HSCT (allo-HSCT) were investigated, AHSCT was preferentially developed due to a more favourable safety profile compared to allo-HSCT. Multiple sclerosis (MS) represents the most frequent neurological indication for AHSCT, but increasing evidence on the potential effectiveness of transplant in other autoimmune neurological diseases is emerging, although with a risk-benefit ratio overall more uncertain than in MS. In the present work, the rationale for the use of HSCT in neurological diseases and the experimental models that prompted its clinical application will be briefly covered. Case series and prospective studies exploring the use of HSCT in autoimmune diseases other than MS will be discussed, covering both frequent and rare neurological disorders such as myasthenia gravis, myopathies, and stiff-person syndrome. Finally, an updated summary of ongoing and future studies focusing on this issue will be provided.

Hematopoietic Stem Cell Transplantation in People With Active Secondary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Uncontrolled evidence suggests that autologous hematopoietic stem cell transplantation (AHSCT) can be effective in people with active secondary progressive multiple sclerosis (SPMS). In this study, we compared the effect of AHSCT with that of other anti-inflammatory disease-modifying therapies (DMTs) on long-term disability worsening in active SPMS. METHODS: We collected data from the Italian Bone Marrow Transplantation Study Group and the Italian Multiple Sclerosis Register. Patients were considered eligible if treatment had been started after the diagnosis of SPMS. Disability worsening was assessed by the cumulative proportion of patients with a 6-month confirmed disability progression (CDP) according to the Expanded Disability Status Scale (EDSS) score. Key secondary endpoints were the EDSS time trend after treatment start and the prevalence of disability improvement over time. Time to first CDP was assessed by means of proportional hazard Cox regression models. A linear mixed model with a time × treatment group interaction was used to assess the longitudinal EDSS time trends. Prevalence of improvement was estimated using a modified Kaplan-Meier estimator and compared between groups by bootstrapping the area under the curve. RESULTS: Seventy-nine AHSCT-treated patients and 1975 patients treated with other DMTs (beta interferons, azathioprine, glatiramer-acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, and alemtuzumab) were matched to reduce treatment selection bias using propensity score and overlap weighting approaches. Time to first CDP was significantly longer in transplanted patients (hazard ratio [HR] = 0.50; 95% CI = 0.31-0.81; p = 0.005), with 61.7% of transplanted patients free from CPD at 5 years. Accordingly, EDSS time trend over 10 years was higher in patients treated with other DMTs than in AHSCT-treated patients (+0.157 EDSS points per year compared with -0.013 EDSS points per year; interaction p < 0.001). Patients who underwent AHSCT were more likely to experience a sustained disability improvement: 34.7% of patients maintained an improvement (a lower EDSS than baseline) 3 years after transplant vs 4.6% of patients treated by other DMTs (p < 0.001). DISCUSSION: The use of AHSCT in people with active SPMS is associated with a slowing of disability progression and a higher likelihood of disability improvement compared with standard immunotherapy. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to CDP compared with other DMTs.

Long-term-video monitoring EEG and 18F-FDG-PET are useful tools to detect residual disease activity in anti-LGI1-Abs encephalitis: A case report.

Background: The use of CD20-depleting monoclonal antibodies has shown to improve the long-term outcome of patients with anti-leucine-rich glioma-inactivated protein 1 antibodies (anti-LGI1-Abs) encephalitis after first-line immunotherapy, but currently predictive markers of treatment response and disease activity are lacking. Case presentation: A 75-year-old man presented cognitive impairment and faciobrachial dystonic seizures (FBDS), with mild abnormalities at electroencephalography (EEG), normal brain magnetic resonance and cerebrospinal fluid (CSF) analysis. Anti-LGI1-Abs were detected in serum and CSF, and corticosteroids and intravenous immunoglobulins were administered. Despite partial cognitive improvement, 18F-fluoridesoxyglucose-positron emission tomography (18F-FDG-PET) showed the persistence of temporo-mesial hypermetabolism, and FBDS were still detected by long-term monitoring video EEG (LTMV EEG). Rituximab was therefore administered with FBDS disappearance, further cognitive improvement, and resolution of 18F-FDG-PET temporo-mesial hypermetabolism. Conclusions: Our experience supports the use of 18F-FDG-PET and LTMVEEG as useful tools to measure disease activity, evaluate treatment response and guide therapeutic decisions in the long-term management of anti-LGI1-antibody encephalitis.

Relevance of Pathogenetic Mechanisms to Clinical Effectiveness of B-Cell-Depleting Monoclonal Antibodies in Multiple Sclerosis.

Evidence of the effectiveness of B-cell-depleting monoclonal antibodies (mAbs) in multiple sclerosis (MS) prompted a partial revisitation of the pathogenetic paradigm of the disease, which was, so far, considered a T-cell-mediated autoimmune disorder. Mechanisms underlying the efficacy of B-cell-depleting mAbs in MS are still unknown. However, they likely involve the impairment of pleiotropic B-cell functions different from antibody secretion, such as their role as antigen-presenting cells during both the primary immune response in the periphery and the secondary response within the central nervous system (CNS). A potential impact of B-cell-depleting mAbs on inflammation compartmentalised within the CNS was also suggested, but little is known about the mechanism underlying this latter phenomenon as no definite evidence was provided so far on the ability of mAbs to cross the blood-brain barrier and reliable biomarkers of compartmentalised inflammation are lacking. The present paper briefly summarises the immunopathogenesis of MS with a focus on onset of autoimmunity and compartmentalisation of the immune response; mechanisms mediating B-cell depletion and underlying the effectiveness of B-cell-depleting mAbs are also discussed.

Investigating Serum sHLA-G Cooperation With MRI Activity and Disease-Modifying Treatment Outcome in Relapsing-Remitting Multiple Sclerosis.

Relapsing-remitting multiple sclerosis (RRMS) is a demyelinating disease in which pathogenesis T cells have a major role. Despite the unknown etiology, several risk factors have been described, including a strong association with human leukocyte antigen (HLA) genes. Recent findings showed that HLA class I-G (HLA-G) may be tolerogenic in MS, but further insights are required. To deepen the HLA-G role in MS inflammation, we measured soluble HLA-G (sHLA-G) and cytokines serum level in 27 patients with RRMS at baseline and after 12 and 24 months of natalizumab (NTZ) treatment. Patients were divided into high (sHLA-G>20 ng/ml), medium (sHLA-G between 10 and 20 ng/ml), and low (sHLA-G <10 ng/ml) producers. Results showed a heterogeneous distribution of genotypes among producers, with no significant differences between groups. A significant decrease of sHLA-G was found after 24 months of NTZ in low producers carrying the +3142 C/G genotype. Finally, 83.3% of high and 100% of medium producers were MRI-activity free after 24 months of treatment, compared to 63.5% of low producers. Of note, we did not find any correlation of sHLA-G with peripheral cell counts or cytokines level. These findings suggest that serum sHLA-G level may partly depend on genotype rather than peripheral inflammation, and that may have impacted on MRI activity of patients over treatment.

Safety and tolerability of SARS-Cov-2 vaccination in patients with myasthenia gravis: A multicenter experience.

BACKGROUND AND PURPOSE: During the COVID-19 pandemic, myasthenia gravis (MG) patients have been identified as subjects at high risk of developing severe COVID-19, and thus were offered vaccination with priority. The lack of direct data on the safety and tolerability of SARS-CoV-2 vaccines in MG have contributed to vaccine hesitancy. To address this issue, the safety and tolerability of SARS-CoV-2 vaccines were assessed in a large cohort of MG patients from two referral centers. METHODS: Patients with confirmed MG diagnosis, consecutively seen between October and December 2021 at two MG centers, were enrolled. Demographics, clinical characteristics, and information regarding SARS-CoV-2 infection/vaccination were extracted from medical reports and/or collected throughout telephonic or in-person interviews. RESULTS: Ninety-eight (94.2%) of 104 patients included were administered at least two vaccine doses 4 weeks before the interview or earlier, and among them, 63 of 98 (64.2%) have already received the "booster" dose. The most frequently used vaccines were BNT162b2-Pfizer-BioNTech and mRNA-1273-Moderna. Overall, only minor side effects were reported, most commonly local pain and fever. MG worsening after vaccination was observed in eight of 104 (7.7%) cases. The frequency of worsening among muscle-specific tyrosine kinase MG cases (3/9, 33.3%) was significantly higher compared to other serological subgroups. Spontaneous symptom regression was observed in six of eight cases. Twelve of 104 (11.5%) patients had SARS-CoV-2 infection, and none of the SARS-CoV-2-infected MG patients worsened after vaccination. CONCLUSIONS: Our data support the safety and tolerability of mRNA COVID-19 vaccines, which should be strongly recommended in MG patients, who could be at higher risk of complications if exposed to SARS-CoV-2 infection.

Intermediate-Intensity Autologous Hematopoietic Stem Cell Transplantation Reduces Serum Neurofilament Light Chains and Brain Atrophy in Aggressive Multiple Sclerosis.

Background: Autologous haematopoietic stem cell transplantation (AHSCT) is highly effective in reducing new inflammatory activity in aggressive multiple sclerosis (MS). A remarkable decrease of serum neurofilament light chains (sNfL) concentration, a marker of axonal damage, was reported in MS following high-intensity regimen AHSCT, but hints for potential neurotoxicity had emerged. sNfL and brain atrophy were therefore analysed in a cohort of patients with aggressive MS treated with intermediate-intensity AHSCT, exploring whether sNfL might be a reliable marker of disability progression independent from new inflammation (i.e. relapses and/or new/gadolinium-enhancing MRI focal lesions). Methods: sNfL concentrations were measured using SIMOA methodology in peripheral blood from relapsing-remitting (RR-) or secondary-progressive (SP-) MS patients undergoing AHSCT (MS AHSCT), collected before transplant and at months 6 and 24 following the procedure. sNfL measured at a single timepoint in SP-MS patients not treated with AHSCT without recent inflammatory activity (SP-MS CTRL) and healthy subjects (HD) were used as controls. The rate of brain volume loss (AR-BVL) was also evaluated by MRI in MS AHSCT cases. Results: Thirty-eight MS AHSCT (28 RR-MS; 10 SP-MS), 22 SP-MS CTRL and 19 HD were included. Baseline median sNfL concentrations were remarkably higher in the MS AHSCT than in the SP-MS CTRL and HD groups (p = 0.005 and <0.0001, respectively), and levels correlated with recent inflammatory activity. After a marginal (not significant) median increase observed at month 6, at month 24 following AHSCT sNfL concentrations decreased compared to baseline by median 42.8 pg/mL (range 2.4-217.3; p = 0.039), reducing by at least 50% in 13 cases, and did not differ from SP-MS CTRL (p = 0.110) but were still higher than in HD (p < 0.0001). Post-AHSCT AR-BVL normalised in 55% of RR-MS and in 30% of SP-MS. The effectiveness and safety of AHSCT were aligned with the literature. Conclusion: sNfL concentrations correlated with recent inflammatory activity and were massively and persistently reduced by intermediate-intensity AHSCT. Association with response to treatment assessed by clinical or MRI outcomes was not observed, suggesting a good sensitivity of sNfL for recent inflammatory activity but low sensitivity in detecting ongoing axonal damage independent from new focal inflammation.

Effect of disease-modifying treatments on antibody-mediated response to anti-COVID19 vaccination in people with multiple sclerosis.

BACKGROUND: Few data are available so far on the antibody-mediated immune response to anti-SARS-Cov2 vaccination in people with multiple sclerosis (pwMS) treated with disease-modifying treatments (DMTs), therefore this issue was explored in a real-life cohort of pwMS. MATERIALS AND METHODS: Retrospective monocentric study on anti-spike protein antibody response in pwMS who had received vaccination for Sars-Cov2. Adverse events following vaccination were also recorded. RESULTS: One hundred and twenty pwMS were included: 83 females (69%); median age at vaccination 42 years (range 21-73); 112/120 patients (93%) were receiving DMTs at vaccination. Anti-spike protein IgG antibodies were detectable in 102/120 (85%) cases overall, being the proportion lower in pwMS receiving anti-CD20 antibodies (14/31, 45%) compared to non-depletive treatments (77/78, 99%), p < 0.0001. Median anti-spike titre was lower in anti-CD20 antibodies and fingolimod-treated pwMS compared to those receiving other DMTs, and it correlated with anti-CD20 treatment duration (R - 0.93, p < 0.0001) and with age at vaccination in pwMS not receiving depletive treatments (R - 0.25, p = 0.028). Baseline CD19+ cell count (where available) was higher in the responder group than in non-responders, p < 0.0001. Two symptomatic COVID-19 infections were diagnosed over a median follow-up of 5 months (range 2-7); adverse events were aligned with the published literature. CONCLUSION: Antibody response to anti-COVID-19 vaccines was detected in most of the pwMS analysed, but frequency of responders was reduced in those receiving CD20 depleting therapies compared to other DMTs-treated pwMS. Investigations on cell-mediated immune response are needed to assess whether a protective immune response is elicited also in non-antibody responders.

Autologous haematopoietic stem cell transplantation versus low-dose immunosuppression in secondary-progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Effectiveness of autologous haematopoietic stem cell transplantation (AHSCT) in relapsing-remitting multiple sclerosis (MS) is well known, but in secondary-progressive (SP)-MS it is still controversial. Therefore, AHSCT activity was evaluated in SP-MS using low-dose immunosuppression with cyclophosphamide (Cy) as a comparative treatment. METHODS: In this retrospective monocentric 1:2 matched study, SP-MS patients were treated with intermediate-intensity AHSCT (cases) or intravenous pulses of Cy (controls) at a single academic centre in Florence. Controls were selected according to baseline characteristics adopting cardinality matching after trimming on the estimated propensity score. Kaplan-Meier and Cox analyses were used to estimate survival free from relapses (R-FS), survival free from disability progression (P-FS), and no evidence of disease activity 2 (NEDA-2). RESULTS: A total of 93 SP-MS patients were included: 31 AHSCT, 62 Cy. Mean follow-up was 99 months in the AHSCT group and 91 months in the Cy group. R-FS was higher in AHSCT compared to Cy patients: at Year 5, 100% versus 52%, respectively (p < 0.0001). P-FS did not differ between the groups (at Year 5: 70% in AHSCT and 81% in Cy, p = 0.572), nor did NEDA-2 (p = 0.379). A sensitivity analysis including only the 31 "best-matched" controls confirmed these results. Three neoplasms (2 Cy, 1 AHSCT) and two fatalities (2 Cy) occurred. CONCLUSIONS: This study provides Class III evidence, in SP-MS, on the superior effectiveness of AHSCT compared to Cy on relapse activity, without differences on disability accrual. Although the suppression of relapses was observed in the AHSCT group only, AHSCT did not show advantages over Cy on disability, suggesting that in SP-MS disability progression becomes based more on noninflammatory neurodegeneration than on inflammation.