Challenges in Diagnosis of COVID-19 Pneumonia under Ocrelizumab and De-Risking Strategies in Multiple Sclerosis-The Elephant Is (Still) in the Room.

Severe SARS-CoV-2 infections may still be observed in people bearing risk factors, such as the use of anti-CD20 monoclonal antibodies (mAbs), which are adopted in several autoimmune disorders including multiple sclerosis (MS). COVID-19 diagnosis is routinely based on nasopharyngeal swab testing, but suboptimal sensitivity for SARS-CoV-2 detection compared to bronchoalveolar lavage (BAL) may lead to misdiagnosis in some cases. Such diagnostic issues were described in a few MS patients receiving anti-CD20 mAbs, including middle-aged people and lacking information on subsequent MS therapeutic management, a debated topic as no evidence-based guidance on de-risking strategies is currently available. Here, we report the case of a young MS patient who developed severe COVID-19 pneumonia under treatment with the anti-CD20 mAb ocrelizumab, and who was finally diagnosed with SARS-CoV-2 by BAL despite repeatedly negative nasopharyngeal swabs. Ocrelizumab was then discontinued, and treatment with a sphingosine-1 phosphate receptor modulator was started, followed by maintenance of clinical and radiological MS stability. Challenges in diagnosing COVID-19 pneumonia in people without risk factors other than immunomodulatory treatment are hence discussed, as well as potential strategies for de-risking MS therapies. The latter topic is increasingly debated based on raising concerns for potential long-term safety issues of high-efficacy treatments, including anti-CD20 mAbs.

Comparative efficacy of subcutaneous versus intravenous natalizumab on annualized relapse rate: A post-hoc analysis of the REFINE study.

BACKGROUND: The non-inferiority of the efficacy of subcutaneous (SC) vs intravenous (IV) administration of natalizumab (NTZ) once every 4 weeks in relapsing-remitting multiple sclerosis (RRMS) was recently demonstrated on the primary outcome of the REFINE study, i.e. MRI "combined unique active lesions number" (CUAL). To provide further evidence on the comparative efficacy of the two NTZ formulations, the effect of NTZ-SC vs NTZ-IV on annualized relapse rate (ARR) was investigated re-analysing the REFINE dataset. METHODS: Post-hoc analysis of the REFINE study dataset aimed at exploring the non-inferiority of the efficacy of NTZ-SC vs NTZ-IV on ARR, i.e. the main secondary outcome of the REFINE study. Robustness of the non-inferiority analysis on CUAL with respect to the presence of cases from the SC arm who received a rescue treatment, including NTZ-IV, was also assessed by sensitivity analyses. Three non-inferiority margins were selected, corresponding to 25 %, 33 %, and 50 % fractions of the effect size of NTZ-IV vs placebo observed in the AFFIRM study on ARR (i.e. 0.125, 0.170, and 0.250). RESULTS: Ninety-nine RRMS patients were included. The mean difference in the effect of NTZ-SC vs NTZ-IV on ARR was close to 0. The lower bound of the 95 % confidence interval (worst case scenario) was -0.119, corresponding to 25 % (p = 0.025) of the effect of NTZ-IV vs placebo on ARR. Sensitivity analyses confirmed the results of the primary non-inferiority analysis on the outcome CUAL. CONCLUSIONS: NTZ-SC resulted not inferior to NTZ-IV on ARR for all the non-inferiority margins. The non-inferiority analysis of the efficacy of NTZ-SC vs NTZ-IV on CUAL was demonstrated to be robust with respect to rescued patients.

Exploring the therapeutic potential of autologous hematopoietic stem cell transplantation in progressive multiple sclerosis-a systematic review.

BACKGROUND AND PURPOSE: The aim was to determine the value of autologous haematopoietic stem cell transplantation (aHSCT) as a therapeutic intervention for progressive multiple sclerosis (PMS) based on a systematic review of the current literature. METHODS: All studies from the databases PubMed and Google Scholar published in English before February 2024 which provided individual data for PMS patients were systematically reviewed. PICO was defined as population (P), primary progressive MS and secondary progressive MS patients; intervention (I), treatment with aHSCT; comparison (C), none, disease-modifying therapy treated/relapsing-remitting MS cohorts if available; outcome (O), transplant-related mortality, progression-free survival (PFS) and no evidence of disease activity. RESULTS: A total of 15 studies met the criteria including 665 patients with PMS (74 primary progressive MS, 591 secondary progressive MS) and 801 patients with relapsing-remitting MS as controls. PFS data were available for 647 patients. PMS patients showed more severe disability at baseline than relapsing-remitting MS patients. The average transplant-related mortality for PMS in 10 studies was 1.9%, with 10 deaths in 528 patients. PFS ranged from 0% to 78% in PMS groups 5 years after treatment initiation, demonstrating a high variability. No evidence of disease activity scores at 5 years ranged from 0% to 75%. CONCLUSION: Based on the available data, aHSCT does not halt progression in people with PMS. However, there appears to be evidence of improved outcome in selected patients. Due to the heterogeneity of the available data, more comprehensive clinical trials assessing the efficacy of aHSCT across different patient groups are urgently needed to reduce variability and improve patient stratification.

The role of chemotherapy in hematopoietic stem cell transplantation for autoimmune disorders: From lymphoablative to myeloablative conditioning protocols.

Hematopoietic stem cell transplantation (HSCT) is a medical procedure used mainly for the treatment of onco-hematologic disorders. Over the last two decades, autologous HSCT has been explored for the treatment of neurologic autoimmune diseases (ADs), being multiple sclerosis (MS) the most frequent indication in this setting. HSCT is characterized by the sequential administration of a conditioning regimen (CR) and the infusion of hematopoietic stem cells (HSCs), previously collected either by the individual himself in the autologous transplant (AHSCT), or by a healthy donor in allogeneic HSCT. CR consists of the administration of high-dose chemotherapy and/or total body irradiation (TBI), that in ADs is usually associated with an immunodepleting serotherapy, either by an animal-derived polyclonal serum or a monoclonal antibody (MoAb), to induce intense immunosuppression. CRs are classified according to the European Society for Blood and Marrow Transplantation (EBMT) guidelines for HSCT in ADs in three grades of intensity according to the degrees of depletion of the hemato-lymphopoietic system induced. In the present chapter, after a brief overview of mobilization and CR adopted in the neurologic autoimmune setting, the role of chemotherapy in HSCT will be discussed, providing a historical perspective on the use of different regimens and summarizing the available evidence on potential associations between CR and outcomes.

Immune cell reconstitution following autologous hematopoietic stem cell transplantation in multiple sclerosis.

Hematopoietic stem cell transplantation (HSCT) is a multistep procedure aimed at eradicating the immune system and replacing it with a new one reconstituted from hematopoietic stem cells which in autologous HSCT (AHSCT) have previously been harvested from the same individual. Over the last two decades, AHSCT has been developed as a treatment option for people affected by aggressive multiple sclerosis (MS), and it exerts a long-standing effect on new inflammation-driven disease activity. The rationale for the use of AHSCT in MS will be discussed, starting from the first observations on experimental models. The mechanisms and kinetics of repopulation (i.e., quantitative recovery) and reconstitution (i.e., qualitative changes) of the immune cell populations will be explored, focusing on immune reconstitution of the T and B cells compartments and briefly covering changes in the innate immune system. Finally, potential immunologic markers of response to treatment will be reviewed. Insights into the supposed mechanism(s) of action of AHSCT will be provided, discussing the leading hypothesis of the "rebuilding" of a newly tolerant immune system, and examining the apparent paradox of the long-standing control of disease activity despite a relatively short-term immunosuppressive effect of the procedure.

Spinal cord size as promising biomarker of disability outcomes after hematopoietic stem cell transplantation in multiple sclerosis.

BACKGROUND: Biomarkers predictive of disability outcomes in individual multiple sclerosis (MS) patients undergoing autologous haematopoietic stem cell transplantation (AHSCT) are currently lacking. As correlations between spinal cord atrophy and clinical disability in MS were previously described, in this study spinal cord size was investigated in MS patients treated with AHSCT, exploring whether baseline spinal cord volume may predict disability progression after AHSCT. METHODS: relapsing-remitting (RR-) and secondary-progressive (SP-) MS patients treated with AHSCT (BEAM/ATG regimen) at a single academic centre in Florence, who performed at least two standardized brain magnetic resonance imaging (MRIs) scans (acquired between one-year pre-AHSCT to 5 years after AHSCT) were included. Cervical spinal cord atrophy was estimated as upper cervical spinal cord cross-sectional area (SCCSA). Brain volume loss (BVL) was analysed at the same timepoints. RESULTS: Eleven (8 RR-; 3 SP-) MS patients were included. Over a median follow-up of 66 (range 37 - 100) months, no relapses nor brain MRI activity were observed; disability progressed in 2 cases (both SP-MS). Baseline SCCSA was associated with EDSS change between pre- and one-year post-AHSCT. Compared to patients who stabilized, patients who progressed after AHSCT tended to have lower SCCSA at C4 level at baseline and year 1 after AHSCT. Longitudinal changes in SCCSA or BVL did not correlate with EDSS change. CONCLUSIONS: Baseline pre-AHSCT SCCSA, but not its longitudinal changes nor BVL, predicted EDSS change within the two years following AHSCT. SCCSA may represent a biomarker of treatment response and a promising screening tool for assessing patient eligibility for high-impact treatments such as AHSCT.

Leptomeningeal enhancement in multiple sclerosis: a focus on patients treated with hematopoietic stem cell transplantation.

Background: Leptomeningeal enhancement (LME) is considered an MRI marker of leptomeningeal inflammation in inflammatory neurological disorders, including multiple sclerosis (MS). To our knowledge, no disease-modifying therapies (DMTs) have been demonstrated to affect LME number or morphology so far. Methods: Monocentric study investigating the frequency and number of LME in a cohort of people with (pw)MS who performed a 3 T brain MRI with a standardized protocol (including a post-contrast FLAIR sequence), and exploring the impact of autologous hematopoietic stem cell transplantation (AHSCT) on this marker. In a longitudinal pilot study, consecutive MRIs were also analyzed in a subgroup of pwMS, including patients evaluated both pre- and post-AHSCT. Results: Fifty-five pwMS were included: 24/55 (44%) had received AHSCT (AHSCT group) and 31 other treatments (CTRL group). At least one LME was identified in 19/55 (35%) cases (42 and 29% in the AHSCT and CTRL groups, respectively; p = 0.405). In the AHSCT group, LME number correlated with age at AHSCT (R = 0.50; p = 0.014), but not with age at post-treatment MRI. In the longitudinal pilot study (n = 8), one LME disappeared following AHSCT in 1/4 patients, whereas LME number was unchanged in the remaining four pwMS from the CTRL group. Discussion: These results suggest that AHSCT may affect development and persistence of LME, strengthening the indication for early use of effective therapies bioavailable within the central nervous system (CNS), and therefore potentially targeting compartmentalized inflammation.

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.

Should autologous hematopoietic stem cell transplantation be offered as a first-line disease modifying therapy to patients with multiple sclerosis?

In multiple sclerosis (MS), progression independent of new focal inflammation may commence shortly after disease onset, and it is increasingly revealed that the risk of disability accrual is reduced by early use of high-efficacy disease-modifying therapies (HE-DMTs). People with aggressive MS may therefore benefit from early treatment with autologous haematopoietic stem cell transplantation (AHSCT), a procedure inducing maximal immunosuppression followed by immune reconstitution, demonstrated to be superior to DMTs in one randomized clinical trial. However, in current practice prior failure to HE-DMTs is typically required to establish the indication for AHSCT. In the present article, the available evidence on the potential role of AHSCT as first-line treatment in aggressive MS and the rationale for its early use will be summarized. Proposed definitions of aggressive MS that could help identifying MS patients eligible for early treatment with AHSCT will also be discussed.

Haematopoietic Stem Cell Transplantation for the Treatment of Multiple Sclerosis: Recent Advances.

PURPOSE OF REVIEW: Autologous haematopoietic stem cell transplantation (AHSCT) is increasingly considered a treatment option for patients with multiple sclerosis (MS), an autoimmune demyelinating and degenerative disease of the central nervous system (CNS). AHSCT persistently suppresses inflammation and improves the disease course in large proportions of patients with relapsing-remitting (RR) MS. Aim of this article is to review the relevant new knowledge published during the last 3 years. RECENT FINDINGS: Laboratory studies reported confirmatory and new insights into the immunological and biomarker effects of AHSCT. Retrospective clinical studies confirmed excellent outcomes in RRMS, showing possible superior effectiveness over standard therapies and suggesting a possible benefit in early secondary progressive (SP) MS with inflammatory features. New data on risks of infertility and secondary autoimmunity were also reported. Further evidence on the high effectiveness and acceptable safety of AHSCT strengthens its position as a clinical option for aggressive RRMS. Further research is needed to better define its role in treatment-naïve and progressive forms of MS, ideally within randomised clinical trials (RCTs).

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.

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.

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.

Antibody-mediated cell depletion therapies in multiple sclerosis.

Development of disease-modifying therapies including monoclonal antibody (mAb)-based therapeutics for the treatment of multiple sclerosis (MS) has been extremely successful over the past decades. Most of the mAb-based therapies approved for MS deplete immune cell subsets and act through activation of cellular Fc-gamma receptors expressed by cytotoxic lymphocytes and phagocytes, resulting in antibody-dependent cellular cytotoxicity or by initiation of complement-mediated cytotoxicity. The therapeutic goal is to eliminate pathogenic immune cell components and to potentially foster the reconstitution of a new and healthy immune system. Ab-mediated immune cell depletion therapies include the CD52-targeting mAb alemtuzumab, CD20-specific therapeutics, and new Ab-based treatments which are currently being developed and tested in clinical trials. Here, we review recent developments in effector mechanisms and clinical applications of Ab-based cell depletion therapies, compare their immunological and clinical effects with the prototypic immune reconstitution treatment strategy, autologous hematopoietic stem cell transplantation, and discuss their potential to restore immunological tolerance and to achieve durable remission in people with MS.

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.