Vaccine Safety and Immunogenicity in Patients With Multiple Sclerosis Treated With Natalizumab.

Importance: Vaccination in patients with highly active multiple sclerosis (MS) requiring prompt treatment initiation may result in impaired vaccine responses and/or treatment delay. Objective: To assess the immunogenicity and safety of inactivated vaccines administered during natalizumab treatment. Design, Setting, and Participants: This self-controlled, prospective cohort study followed adult patients with MS from 1 study center in Spain from September 2016 to February 2022. Eligible participants included adults with MS who completed immunization for hepatitis B virus (HBV), hepatitis A virus (HAV), and COVID-19 during natalizumab therapy. Data analysis was conducted from November 2022 to February 2023. Exposures: Patients were categorized according to their time receiving natalizumab treatment at the time of vaccine administration as short-term (≤1 year) or long-term (>1 year). Main Outcomes and Measures: Demographic, clinical, and radiological characteristics were collected during the year before vaccination (prevaccination period) and the year after vaccination (postvaccination period). Seroprotection rates and postvaccination immunoglobulin G titers were determined for each vaccine within both periods. Additionally, differences in annualized relapse rate (ARR), new T2 lesions (NT2L), Expanded Disability Status Scale (EDSS) scores, and John Cunningham virus (JCV) serostatus between the 2 periods were assessed. Results: Sixty patients with MS (mean [SD] age, 43.2 [9.4] years; 44 female [73.3%]; 16 male [26.7%]; mean [SD] disease duration, 17.0 [8.7] years) completed HBV, HAV, and mRNA COVID-19 immunization during natalizumab treatment, with 12 patients in the short-term group and 48 patients in the long-term group. The global seroprotection rate was 93% (95% CI, 86%-98%), with individual vaccine rates of 92% for HAV (95% CI, 73%-99%), 93% for HBV (95% CI, 76%-99%), and 100% for the COVID-19 messenger RNA vaccine (95% CI, 84%-100%). Between the prevaccination and postvaccination periods there was a significant reduction in the mean (SD) ARR (0.28 [0.66] vs 0.01 [0.12]; P = .004) and median (IQR) NT2L (5.00 [2.00-10.00] vs 0.81 [0.00-0.50]; P = .01). No changes in disability accumulation were detected (median [IQR] EDSS score 3.5 [2.0-6.0] vs 3.5 [2.0-6.0]; P = .62). No differences in safety and immunogenicity were observed for all vaccines concerning the duration of natalizumab treatment. Conclusions and Relevance: The findings of this cohort study suggest that immunization with inactivated vaccines during natalizumab therapy was both safe and immunogenic, regardless of the treatment duration. Natalizumab may be a valuable option for proper immunization, averting treatment delays in patients with highly active MS; however, this strategy needs to be formally evaluated.

Safety and efficacy of extended versus standard interval dosing of natalizumab in multiple sclerosis patients: a systematic review and meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory, immune-mediated disease affecting the central nervous system. Natalizumab, an FDA-approved monoclonal antibody for MS, has been explored for its off-label extended interval dosing (EID), suggesting a potential reduction in the risk of progressive multifocal leukoencephalopathy (PML) compared to standard interval dosing (SID). Our objective was to assess the efficacy and safety of EID in comparison to SID for natalizumab treatment in patients with MS. METHODS: We searched PubMed, Embase, WOS, Scopus, Ovid, Science Direct, Clinical trials.gov, and Cochrane Library. Our assessed outcomes were clinical relapses, MRI activity, change in expanded disability status scale [EDSS], and the risk of PML. The EID group was defined as 5 to 8 weeks [EID (Q5-8W)]. The analysis was conducted using RevMan ver. 5.4. The effect estimates were presented as a risk ratio [RR] or mean difference with 95% confidence intervals [CI] using SID group as the reference for comparisons. RESULTS: Fourteen studies met our inclusion criteria: 2 RCTs, 1 switched single-arm trial, and 12 observational studies. No significant differences were found in all efficacy outcomes of interest. Risk of clinical relapses [RR = 0.90, (95%CI 0.80, 1.02)], risk of new or newly enlarging T2 hyperintense MRI lesions [RR = 0.78, (95%CI 0.59, 1.04)], risk gadolinium enhancing lesions [RR = 1.30, (95%CI 0.98, 1.72)], change in EDSS [MD = 0.09 (95%CI - 0.57, 0.76)], risk of PML [RR = 1.09, 95%CI (0.24, 4.94)]. CONCLUSION: In summary, our meta-analysis indicates that natalizumab maintains its effectiveness under extended interval dosing [up to 8 weeks], presenting comparable risks for clinical relapses, MRI lesions, EDSS, and PML. Caution is advised given study limitations and heterogeneity. Robust conclusions necessitate well-designed high-quality prospective studies.

Immunosenescence and vaccine efficacy revealed by immunometabolic analysis of SARS-CoV-2-specific cells in multiple sclerosis patients.

Disease-modifying therapies (DMT) administered to patients with multiple sclerosis (MS) can influence immune responses to SARS-CoV-2 and vaccine efficacy. However, data on the detailed phenotypic, functional and metabolic characteristics of antigen (Ag)-specific cells following the third dose of mRNA vaccine remain scarce. Here, using flow cytometry and 45-parameter mass cytometry, we broadly investigate the phenotype, function and the single-cell metabolic profile of SARS-CoV-2-specific T and B cells up to 8 months after the third dose of mRNA vaccine in a cohort of 94 patients with MS treated with different DMT, including cladribine, dimethyl fumarate, fingolimod, interferon, natalizumab, teriflunomide, rituximab or ocrelizumab. Almost all patients display functional immune response to SARS-CoV-2. Different metabolic profiles characterize antigen-specific-T and -B cell response in fingolimod- and natalizumab-treated patients, whose immune response differs from all the other MS treatments.

Twin study dissects CXCR3+ memory B cells as non-heritable feature in multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), B cells are considered main triggers of the disease, likely as the result of complex interaction between genetic and environmental risk factors. Studies on monozygotic twins discordant for MS offer a unique way to reduce this complexity and reveal discrepant subsets. METHODS: In this study, we analyzed B cell subsets in blood samples of monozygotic twins with and without MS using publicly available data. We verified functional characteristics by exploring the role of therapy and performed separate analyses in unrelated individuals. FINDINGS: The frequencies of CXCR3+ memory B cells were reduced in the blood of genetically identical twins with MS compared to their unaffected twin siblings. Natalizumab (anti-VLA-4 antibody) was the only treatment regimen under which these frequencies were reversed. The CNS-homing features of CXCR3+ memory B cells were supported by elevated CXCL10 levels in MS cerebrospinal fluid and their in vitro propensity to develop into antibody-secreting cells. CONCLUSIONS: Circulating CXCR3+ memory B cells are affected by non-heritable cues in people who develop MS. This underlines the requirement of environmental risk factors such as Epstein-Barr virus in triggering these B cells. We propose that after CXCL10-mediated entry into the CNS, CXCR3+ memory B cells mature into antibody-secreting cells to drive MS. FUNDING: This work was supported by Nationaal MS Fonds (OZ2021-016), Stichting MS Research (19-1057 MS, 20-490f MS, and 21-1142 MS), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program grant agreement no. 882424, and the Swiss National Science Foundation (733 310030_170320, 310030_188450, and CRSII5_183478).

Comparative Effectiveness of Natalizumab, Fingolimod, and Injectable Therapies in Pediatric-Onset Multiple Sclerosis: A Registry-Based Study.

BACKGROUND AND OBJECTIVES: Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses, and though patients with POMS usually recover from relapses better than adults, patients with POMS reach irreversible disability at a younger age than adult-onset patients. There have been few randomized, placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry. METHODS: This retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021. Patients were matched using inverse probability treatment weighting. The primary outcome was time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement. RESULTS: A total of 1,218 patients with POMS were included in this analysis. Patients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMTs (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29-0.83; p = 0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMTs (HR, 0.15; 95% CI 0.07-0.31; p < 0.001) or fingolimod (HR, 0.37; 95% CI 0.14-1.00; p = 0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting-adjusted patient populations were confirmed in multiple sensitivity analyses. DISCUSSION: Our analyses of relapse risk suggest that natalizumab is more effective than fingolimod in the control of relapses in this population with high rates of new inflammatory activity, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. In addition, both fingolimod and natalizumab were more effective than first-line injectable therapies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that patients with POMS treated with natalizumab had a lower risk of relapse than those with fingolimod.

Natalizumab promotes anti-inflammatory and repair effects in multiple sclerosis.

BACKGROUND: Multiple sclerosis is an inflammatory and degenerative disease of the central nervous system leading to demyelination and axonal loss. Relapsing-remitting multiple sclerosis (RRMS) is commonly treated by anti-inflammatory drugs, where one of the most effective drugs to date is the monoclonal antibody natalizumab. METHODS: The cerebrospinal fluid (CSF) proteome was analyzed in 56 patients with RRMS before and after natalizumab treatment, using label-free mass spectrometry and a subset of the changed proteins were verified by parallel reaction monitoring in a new cohort of 20 patients, confirming the majority of observed changes. RESULTS: A total of 287 differentially abundant proteins were detected including (i) the decrease of proteins with roles in immunity, such as immunoglobulin heavy constant mu, chitinase-3-like protein 1 and chitotriosidase, (ii) an increase of proteins involved in metabolism, such as lactate dehydrogenase A and B and malate-dehydrogenase cytoplasmic, and (iii) an increase of proteins associated with the central nervous system, including lactadherin and amyloid precursor protein. Comparison with the CSF-PR database provided evidence that natalizumab counters protein changes commonly observed in RRMS. Furthermore, vitamin-D binding protein and apolipoprotein 1 and 2 were unchanged during treatment with natalizumab, implying that these may be involved in disease activity unaffected by natalizumab. CONCLUSIONS: Our study revealed that some of the previously suggested biomarkers for MS were affected by the natalizumab treatment while others were not. Proteins not previously suggested as biomarkers were also found affected by the treatment. In sum, the results provide new information on how the natalizumab treatment impacts the CSF proteome of MS patients, and points towards processes affected by the treatment. These findings ought to be explored further to disclose potential novel disease mechanisms and predict treatment responses.

[Pregnancy and breastfeeding in women with multiple sclerosis]. / Schwangerschaft und Stillzeit bei Frauen mit Multipler Sklerose.

The diagnosis of multiple sclerosis (MS) in women of reproductive age is associated with many uncertainties regarding childbearing and lactation. Pregnancies of MS patients are not usually considered high-risk pregnancies per se. The likelihood of pregnancy complications or adverse pregnancy outcomes is not increased by the disease; however, a careful planning of pregnancy is important in order to choose the treatment option with the greatest benefit for the mother and the least possible risk for the baby. For highly active courses of the disease, anti-CD20 antibodies, cladribine, or continued administration of natalizumab show the best data. Patients with MS can be supported in their desire to breastfeed. If women have had a very active disease course, it is recommended that treatment should be started as soon as possible postpartum. Interferon-beta preparations, glatiramer acetate and ofatumumab are also approved for use during breastfeeding but off-label breastfeeding is also possible with other monoclonal antibodies.

Concurrent glioma and multiple sclerosis: A systematic review of case reports.

BACKGROUND: It is uncommon for individuals with demyelinating disease, notably multiple sclerosis (MS), to be diagnosed with intracranial gliomas. It has been debated whether or not the concurrence of these two disorders is accidental. Clinically, it may be challenging to diagnose someone who has MS and an intracranial tumor simultaneously. We conducted this systematic review to evaluate the glioma patients following MS. METHODS: We collected 63 studies from 1672 databases from January 1990 to February 2023, and our inclusion criteria involved peer-reviewed case reports/series studies reporting concurrent MS and glioma in patients, considering various types of gliomas. RESULTS: We included 145 cases, 51% were women and 49 % were men, with an average age of 47.4 years. Common symptoms of glioma at admission included seizures (31.2 %), hemiparesis (15.6 %), and headache (14.3 %). 75 % of patients had primarily with relapsing-remitting MS (RRMS). MS treatments included interferon(IFN)-ß (44.6 %), glatiramer acetate (GA) (21.4 %), fingolimod (19.6 %), and natalizumab (19.6 %). The average time between MS and glioma diagnosis was 12.1 years, with various timeframes. Among the 59 reported cases, 45.8 % led to patient fatalities, while the remaining 54.2 % managed to survive. CONCLUSION: This co-occurrence, though rare, suggests potential underlying shared mechanisms or vulnerabilities, possibly at a genetic or environmental level. An interdisciplinary approach, combining the expertise of neurologists, oncologists, radiologists, and pathologists, is vital to ensure accurate diagnosis and optimal management of affected individuals. Nonetheless, there is still a significant lack of information regarding this phenomenon, necessitating large-scale population-based studies and experimental research.

Natalizumab extended interval dosing: what about wearing-off effect?

BACKGROUND: Up to two thirds of patients with multiple sclerosis (MS) under natalizumab report a resurgence of symptoms at the end of the natalizumab cycle (wearing-off (WO) effect). At the outbreak of COVID-19, in line with the international recommendations for MS management, our centre switched all clinically stable patients on natalizumab therapy for more than one year from standard interval dosing (SID) to extended interval dosing (EID) with every six weeks infusions. This study aimed to evaluate the impact of EID in WO in MS patients under natalizumab. METHODS: An observational retrospective study in patients with MS under natalizumab on EID was conducted. A questionnaire regarding current (on EID) and past (on SID) experience of WO effect was applied. RESULTS: Seventy-six patients were included. No significant differences were found in the annual relapse rate after the switch to EID (p = 0.083). However, there was a significant increase in the proportion of patients complaining of WO from 38.2% to 56.6% (p = 0.001). Moreover, patients with WO on SID, referred a significant increase in severity (p = 0.019) and duration of WO symptoms (p = 0.029), due to an anticipation of the symptoms relative to the day of natalizumab infusion (p = 0.019), when switching to EID. Symptoms improved with treatment maintenance in 23.3% of patients; instead, a reduction in interval dosing was needed in 54.8% with symptom improvement. CONCLUSION: WO affects a significant proportion of MS patients under natalizumab. Its prevalence, severity, and duration increase on EID, therefore despite clinical effectiveness maintenance of this posology should be individualized.

Plasma antioxidant potential measured by total radical trapping antioxidant parameter in a cohort of multiple sclerosis patients.

BACKGROUND: Oxidative injury has been implicated as a mediator of demyelination, axonal damage, and neurodegeneration in multiple sclerosis (MS). There is a high demand for oxidative injury biomarkers. The aim of the study was to evaluate MS patients' plasma antioxidant potential using the total radical trapping parameter (TRAP) assay and examine its usefulness as an MS disease biomarker. METHODS: A total number of 112 MS patients underwent an analysis of TRAP. In addition, plasma uric acid (UA) levels were analyzed. The neurological and radiological data were collected from patient records from Helsinki University Hospital during 2012-2013 when first-line injectables of moderate-efficacy, natalizumab (NTZ), and fingolimod (FTY) of high efficacy disease modifying therapies and in some cases azathioprine (AZT) were used to treat MS. RESULTS: TRAP values were negatively associated with expanded disability status scale (EDSS) score with p-value .052, ß = -28. There was also a negative association in TRAP values between patients with no medication (n = 22, TRAP mean 1255 µmol/L (95% confidence interval [CI] 1136-1374)) and patients who received NTZ, p-value .020 (n = 19, TRAP mean was 991 µmol/L (95% CI 849-1133) or FTY treatment, p-value .030 (n = 5, TRAP mean 982 µmol/L (95% CI 55-1909). Due to a small sample size, these results were not significant after applying a false discovery rate correction at a 0.05 significance level but are worth highlighting. Men in the study had higher TRAP values, p-value = .001 (TRAP mean 1320 ± 293 µmol/L) than women (TRAP mean 1082 ± 288 µmol/L). UA was positively associated with TRAP values, p-value <.001 and UA levels in men (UA mean 334.5 ± 62.6 µmol/L) were higher compared to women (UA mean 240 ± 55.8 µmol/L), t-test p-value <.001. The significant difference in TRAP levels between genders, with men showing higher TRAP values than women, may be attributed to the variation in UA levels. CONCLUSION: Our findings suggest that lower plasma antioxidant potential is linked to more severe disability measured by EDSS scores. Patients treated with NTZ and FTY had reduced antioxidant power, which might be influenced by the active MS disease rather than the treatments themselves. The study reveals a strong positive correlation between UA levels and TRAP, particularly among women. However, men on average had better antioxidant potential than women. Neither the disease type nor the duration influences TRAP levels. While serving as a marker of antioxidant potential, plasma TRAP in MS patients does not reliably reflect overall oxidative stress (OS) and should not be solely used as an indicator of OS.

Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis.

INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) was first described among patients affected by hematological or solid tumors. Following the human immunodeficiency virus (HIV) epidemic, people living with HIV have represented most cases for more than a decade. With the diffusion of highly active antiretroviral therapy, this group progressively decreased in favor of patients undergoing treatment with targeted therapy/immunomodulators. In this systematic review and meta-analysis, the objective was to assess which drugs are most frequently related to PML development, and report the incidence of drug-induced PML through a meta-analytic approach. METHODS: The electronic databases MEDLINE, EMBASE, ClinicalTrials.gov, Web of Science and the Canadian Agency for Drugs and Technologies in Health Database (CADTH) were searched up to May 10, 2022. Articles that reported the risk of PML development after treatment with immunomodulatory drugs, including patients of both sexes under the age of 80 years, affected by any pathology except HIV, primary immunodeficiencies or malignancies, were included in the review. The incidence of drug-induced PML was calculated based on PML cases and total number of patients observed per 100 persons and the observation time. Random-effect metanalyses were conducted for each drug reporting pooled incidence with 95% confidence intervals (CI) and median (interquartile range [IQR]) of the observation time. Heterogeneity was measured by I2 statistics. Publication bias was examined through funnel plots and Egger's test. RESULTS: A total of 103 studies were included in the systematic review. In our analysis, we found no includible study reporting cases of PML during the course of treatment with ocrelizumab, vedolizumab, abrilumab, ontamalimab, teriflunomide, daclizumab, inebilizumab, basiliximab, tacrolimus, belimumab, infliximab, firategrast, disulone, azathioprine or danazole. Dalfampridine, glatiramer acetate, dimethyl fumarate and fingolimod show a relatively safe profile, although some cases of PML have been reported. The meta-analysis showed an incidence of PML cases among patients undergoing rituximab treatment for multiple sclerosis (MS) of 0.01 cases/100 persons (95% CI - 0.08 to 0.09; I2 = 20.4%; p = 0.25) for a median observation period of 23.5 months (IQR 22.1-42.1). Treatment of MS with natalizumab carried a PML risk of 0.33 cases/100 persons (95% CI 0.29-0.37; I2 = 50%; p = 0.003) for a median observation period of 44.1 months (IQR 28.4-60) and a mean number of doses of 36.3 (standard deviation [SD] ± 20.7). When comparing data about patients treated with standard interval dosing (SID) and extended interval dosing (EID), the latter appears to carry a smaller risk of PML, that is, 0.08 cases/100 persons (95% CI 0.0-0.15) for EID versus 0.3 cases/100 persons (95% CI 0.25-0.34) for SID. CONCLUSIONS: A higher risk of drug-related PML in patients whose immune system is not additionally depressed by means of neoplasms, HIV or concomitant medications is found in the neurological field. This risk is higher in MS treatment, and specifically during long-term natalizumab therapy. While this drug is still routinely prescribed in this field, considering the efficacy in reducing MS relapses, in other areas it could play a smaller role, and be gradually replaced by other safer and more recently approved agents.

Imaging Very Late Antigen-4 on MOLT4 Leukemia Tumors with Cysteine Site-Specific 89Zr-Labeled Natalizumab Immuno-Positron Emission Tomography.

Very late antigen-4 (VLA4; CD49d) is a promising immune therapy target in treatment-resistant leukemia and multiple myeloma, and there is growing interest in repurposing the humanized monoclonal antibody (Ab), natalizumab, for this purpose. Positron emission tomography with radiolabeled Abs (immuno-PET) could facilitate this effort by providing information on natalizumab's in vivo pharmacokinetic and target delivery properties. In this study, we labeled natalizumab with 89Zr specifically on sulfhydryl moieties via maleimide-deferoxamine conjugation. High VLA4-expressing MOLT4 human T cell acute lymphoblastic leukemia cells showed specific 89Zr-natalizumab binding that was markedly blocked by excess Ab. In nude mice bearing MOLT4 tumors, 89Zr-natalizumab PET showed high-contrast tumor uptake at 7 days postinjection. Biodistribution studies confirmed that uptake was the highest in MOLT4 tumors (2.22 ± 0.41%ID/g) and the liver (2.33 ± 0.76%ID/g), followed by the spleen (1.51 ± 0.42%ID/g), while blood activity was lower at 1.12 ± 0.21%ID/g. VLA4-specific targeting in vivo was confirmed by a 58.1% suppression of tumor uptake (0.93 ± 0.15%ID/g) when excess Ab was injected 1 h earlier. In cultured MOLT4 cells, short-term 3 day exposure to the proteasome inhibitor bortezomib (BTZ) did not affect the α4 integrin level, but BTZ-resistant cells that survived the treatment showed increased α4 integrin expression. When the effects of BTZ treatment were tested in mice, there was no change of the α4 integrin level or 89Zr-natalizumab uptake in MOLT4 leukemia tumors, which underscores the complexity of tumor VLA4 regulation in vivo. In conclusion, 89Zr-natalizumab PET may be useful for noninvasive monitoring of tumor VLA4 and may assist in a more rational application of Ab-based therapies for hematologic malignancies.

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.

BACKGROUND: Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015. OBJECTIVES: To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS. SEARCH METHODS: CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022. SELECTION CRITERIA: Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach. MAIN RESULTS: We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence). AUTHORS' CONCLUSIONS: We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects.

Varicella Zoster Associated Vasculopathy and Retinitis with Natalizumab Use in Multiple Sclerosis.

Natalizumab (Tysabri®, NTZ) is a monoclonal autoantibody approved for treatment of relapsing-remitting multiple sclerosis. NTZ inhibits leukocyte migration across the blood-brain barrier, preventing autoreactive cells from inciting an inflammatory immune response. This immunosuppression is highly efficacious in attenuating the risk of relapse of disease, but has been associated with opportunistic central nervous system (CNS) infections, most notably progressive multifocal leukoencephalopathy. Varicella-zoster and herpes simplex viruses have also been associated with NTZ, inciting a spectrum of disease, including encephalitis, meningitis, and acute retinal necrosis. While rare, these infections can result in devastating outcomes even when promptly identified and treated.   We present a case of combined CNS varicella zoster vasculitis and acute retinal necrosis in a 57-year-old woman maintained on monthly Natalizumab therapy, who presented with headache and visual field deficits.

Exploring the effects of extended interval dosing of natalizumab and drug concentrations on brain atrophy in multiple sclerosis.

BACKGROUND: Extended interval dosing (EID) of natalizumab treatment is increasingly used in multiple sclerosis. Besides the clear anti-inflammatory effect, natalizumab is considered to have neuroprotective properties as well. OBJECTIVES: This study aimed to study the longitudinal effects of EID compared to standard interval dosing (SID) and natalizumab drug concentrations on brain atrophy. METHODS: Patients receiving EID or SID of natalizumab with a minimum radiological follow-up of 2 years were included. Changes in brain atrophy measures over time were derived from clinical routine 3D-Fluid Attenuated Inversion Recovery (FLAIR)-weighted magnetic resonance imaging (MRI) scans using SynthSeg. RESULTS: We found no differences between EID (n = 32) and SID (n = 50) for whole brain (-0.21% vs -0.16%, p = 0.42), ventricular (1.84% vs 1.13%, p = 0.24), and thalamic (-0.32% vs -0.32%, p = 0.97) annualized volume change over a median follow-up of 3.2 years. No associations between natalizumab drug concentration and brain atrophy rate were found. CONCLUSION: We found no clear evidence that EID compared to SID or lower natalizumab drug concentrations have a negative impact on the development of brain atrophy over time.

Use of multiple sclerosis disease-modifying therapies during pregnancy in France: Nationwide study between 2010 and 2021.

BACKGROUND: Multiple sclerosis (MS) frequently affects women of childbearing age and pregnant women. OBJECTIVE: To assess the use of MS disease-modifying therapies (DMTs) during pregnancy in France over the last decade, marked by an increasing DMTs availability. METHODS: All pregnancies ended from April 2010 to December 2021 in women with MS were identified based on the nationwide Mother-Child Register EPI-MERES, built from the French National Health Data System (Système National des Données de Santé (SNDS)). RESULTS: Of a total of 20,567 pregnancies in women with MS, 7587 were exposed to DMT. The number of DMT-exposed pregnancies markedly increased from 1079 in 2010-2012 to 2413 in 2019-2021 (+124%), especially those exposed to glatiramer acetate, natalizumab, dimethyl fumarate, and anti-CD20. Among pregnancies of women on DMT 6 months before pregnancy, 78.0% underwent DMT discontinuation and 7.6% switched DMT, generally before (33.0% and 77.0%, respectively) or during the first trimester of pregnancy (58.3% and 17.8%, respectively). DMT discontinuation decreased from 84.0% in 2010-2012 to 72.4% in 2019-2021 and was less frequent among women aged ⩾35 years and those socioeconomically disadvantaged. CONCLUSION: Despite MS therapeutic management adaptations to pregnancy, exposure during pregnancy to treatments whose safety profile has not yet been clearly established has increased sharply over the last decade.

Risk of cardiovascular disease in patients with multiple sclerosis treated with fingolimod compared to natalizumab: A nationwide cohort study of 2095 patients in Denmark.

BACKGROUND: Fingolimod may be associated with risk of developing cardiovascular disease (CVD). Studies including reference groups and long follow-up are scarce. OBJECTIVES: We hypothesized that patients treated with fingolimod would be at higher risk of developing CVD compared to patients treated with natalizumab. METHODS: A nationwide 12-year cohort study linking individual-level data from the Danish Multiple Sclerosis Registry with health registries on 2095 adult patients with multiple sclerosis (MS) without any health records of CVD at follow-up start. Exposure to fingolimod and natalizumab was defined by the first treatment of at least 3 months. Cohort entry was from 2011 to 2018. We defined CVD as a composite measure, including hypertension, ischemic heart disease, atrial fibrillation, heart failure, and stroke. We used multivariable adjusted Cox regression. RESULTS: There were 28.8 and 17.4 CVD events per 1000 person-years in fingolimod and natalizumab groups, respectively. Compared to natalizumab-treated patients, fingolimod-treated patients had a higher risk of CVD (hazard ratio (HR) = 1.57; 95% confidence interval (CI) = 1.18-2.08). Hypertension comprised 200 of 244 CVD events. CONCLUSION: We found an increased risk of CVD in patients with MS treated with fingolimod. This increased risk was mainly due to hypertension.

Quantifying the administration and monitoring time burden of several disease-modifying therapies for relapsing multiple sclerosis in the United Kingdom: A time and motion study.

BACKGROUND: The treatment landscape for relapsing multiple sclerosis (MS) has changed dramatically in recent decades, including an increasing number of high-efficacy disease-modifying therapies (DMTs) with varied administration and monitoring requirements. Coupled with greater focus on earlier treatment, these factors have resulted in stretching of the capacity of MS specialist services and allied healthcare professionals (HCPs). To assist with the effective planning of MS services in the UK NHS, this study quantified the administration and monitoring time burden associated with high-efficacy DMTs (alemtuzumab, cladribine tablets, fingolimod, natalizumab, and ocrelizumab) for relapsing MS. METHODS: A Time and Motion (T&M) study was conducted across four MS centres in the UK, over 3-4 months per centre (Aug 2019-Feb 2021). Time dedicated by HCPs (including but not limited to neurologists, MS specialist nurses, infusion nurses, and healthcare assistants) to pre-specified drug administration and monitoring activities, elicited during pre-study interviews at each centre, was assessed for each of the selected DMTs. Administration activities included: installing peripheral access; pre-medication administration (if needed); preparing drug for infusion; infusion initiation, monitoring, and disconnection; and patient monitoring post-infusion. Monitoring activities included: booking appointments for blood draws; blood draw; retrieval and review of blood results; maintaining blood records and follow-up with the patient; checking availability of MRI results and follow-up with the patient; booking appointments for neurologist or nurse consultations; and checking patient files prior to clinic visits. A T&M model was built using observational T&M study results, data obtained through pre-study interviews, as well as stipulated monitoring intervals from relevant Summaries of Product Characteristics for the selected DMTs, to estimate active HCP time with each DMT, extrapolated over a period of 4 years per-patient. RESULTS: For oral DMTs, projected total active HCP time (monitoring only) per-patient over 4 years was 14.7 h for cladribine tablets and 19.2 h for fingolimod. For infused DMTs, total time (administration and monitoring) for alemtuzumab was 37.7 h (6.0 and 31.6 h, respectively), 48.1 h for natalizumab (17.4 and 30.8 h, respectively), and 23.5 h for ocrelizumab (6.1 and 17.4 h, respectively). CONCLUSIONS: While active HCP time varied across centres, infused DMTs were projected to require the greatest amount of HCP time associated with administration and monitoring over 4 years versus oral DMTs. These findings may assist MS-specific HCPs in planning and delivering the equitable provision of DMT services for patients with relapsing MS.