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<jats:sec><jats:title>Background:</jats:title><jats:p> The role of vaccine-mediated inflammation in exacerbating multiple sclerosis (MS) is a matter of debate. </jats:p></jats:sec><jats:sec><jats:title>Objective:</jats:title><jats:p> In this cross-sectional study, we compared the cerebrospinal fluid (CSF) inflammation associated with MS relapses or anti-COVID-19 mRNA vaccinations in relapsing-remitting multiple sclerosis (RRMS). </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> We dosed CSF cytokines in 97 unvaccinated RRMS patients with clinical relapse within the last 100 days. In addition, we enrolled 29 stable RRMS and 24 control patients receiving COVID-19 vaccine within the last 100 days. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> In RRMS patients, a negative association was found between relapse distance and the CSF concentrations of the pro-inflammatory cytokines interleukin (IL)-2 (beta = −0.265, p = 0.016), IL-6 (beta = −0.284, p = 0.01), and IL-17 (beta = −0.224, p = 0.044). Conversely, vaccine distance positively correlated with a different set of cytokines including IL-12 (beta = 0.576, p = 0.002), IL-13 (beta = 0.432, p = 0.027), and IL-1ra (beta = 0.387, p = 0.05). These associations were significant also considering other clinical characteristics. No significant associations emerged between vaccine distance and CSF molecules in the control group. </jats:p></jats:sec><jats:sec><jats:title>Conclusion:</jats:title><jats:p> Vaccine for COVID-19 induces a central inflammatory response in RRMS patients that is qualitatively different from that associated with disease relapse. </jats:p></jats:sec>

<jats:p> The vaccination with live attenuated vaccines is generally not recommended during natalizumab (NTZ), as it is included among immunosuppressive/immunomodulating therapies. Nevertheless, considering the lack of evidence of a non-Central Nervous System (CNS) immunosuppressive effect of NTZ, after a risk/benefit evaluation, we decided to vaccinate four multiple sclerosis (MS) patients (three with an indication to switch to ocrelizumab for high-risk Progressive Multifocal Leukoencephalopathy (PML) and one for pregnancy planning). No vaccine-related adverse events of any type nor varicella zoster virus (VZV) infections were observed. To the best of our knowledge, these case series represent the first description of the good safety profile of anti-VZV vaccination in MS patients during NTZ treatment. </jats:p>

<jats:sec><jats:title>Background:</jats:title><jats:p> Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein not previously described in the human central nervous system (CNS). </jats:p></jats:sec><jats:sec><jats:title>Objectives:</jats:title><jats:p> We determined MFAP4 CNS expression and measured cerebrospinal fluid (CSF) and serum levels. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> Tissue was sampled at autopsy from patients with acute multiple sclerosis (MS) ( n = 3), progressive MS ( n = 3), neuromyelitis optica spectrum disorder (NMOSD) ( n = 2), and controls ( n = 9), including 6 healthy controls (HC). MFAP4 levels were measured in 152 patients: 49 MS, 62 NMOSD, 22 myelin oligodendrocyte glycoprotein-associated disease (MOGAD), and 19 isolated optic neuritis (ION). </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> MFAP4 localized to meninges and vascular/perivascular spaces, intense in the optic nerve. At sites of active inflammation, MFAP4 reactivity was reduced in NMOSD and acute MS and less in progressive MS. CSF MFAP4 levels were reduced during relapse and at the onset of diseases (mean U/mL: MS 14.3, MOGAD 9.7, and ION 14.6 relative to HC 17.9. ( p = 0.013, p = 0.000, and p = 0.019, respectively). Patients with acute ON ( n = 68) had reduced CSF MFAP4 (mean U/mL: 14.5, p = 0.006). CSF MFAP4 levels correlated negatively with relapse severity (rho = −0.41, p = 0.017). </jats:p></jats:sec><jats:sec><jats:title>Conclusion:</jats:title><jats:p> MFAP4 immunoreactivity was reduced at sites of active inflammation. CSF levels of MFAP4 were reduced following relapse and may reflect disease activity. </jats:p></jats:sec>

<jats:p> Risk concerns related to ocrelizumab treatment for multiple sclerosis (MS) during the COVID-19 pandemic caused infusion delays with extended interval dosing (EID). We reviewed medical records of patients on ocrelizumab to determine whether EID maintains its effectiveness compared to standard interval dosing (SID). Among 361 patients, 231 (64%) and 123 (34%) had at least one infusion with infusion intervals of ⩾8 months and ⩾12 months, respectively. There were no differences in demographics or clinical profiles between the SID and EID groups. No significant differences between rates of breakthrough activity among relapsing-remitting patients were observed between SID (three patients) and EID (seven patients). </jats:p>

<jats:sec><jats:title>Background:</jats:title><jats:p> Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct demyelinating disease of the central nervous system. Immunoglobulin (Ig) has been used as a maintenance therapy to prevent relapses in MOGAD, but the impact of Ig on serum MOG-IgG titers is unclear. </jats:p></jats:sec><jats:sec><jats:title>Objective:</jats:title><jats:p> To characterize the variation in serum MOG-IgG titers after initiation of Ig treatment in people with MOGAD. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> We conducted a retrospective study of 10 patients with a diagnosis of MOGAD and available serum MOG-IgG titers before and after initiation of maintenance Ig treatment. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> We found that most of the patients remained MOG-IgG seropositive while on Ig treatment with a reduced or unchanged titer, despite a lack of disease activity. </jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p> This case series suggests that the mechanism of action of Ig therapy in MOGAD is not exclusively dependent on MOG-IgG titer reduction. </jats:p></jats:sec>

<jats:p> Multiple sclerosis (MS) is most likely to adopt a progressive clinical course during middle age or beyond, and the number of older adults with MS is steadily increasing. Developing new strategies to manage progressive forms of MS, which do not respond to currently available disease-modifying therapies (DMTs), will require a deeper understanding of the mechanisms by which biological aging interacts with pathogenic pathways to propel disability accumulation. In experimental autoimmune encephalomyelitis (EAE), a widely used preclinical mouse model of MS, middle-aged animals experience a more severe and protracted clinical course than their younger counterparts. This exacerbated disease course is accompanied by persistent neuroinflammation. Clinical studies of age-related biomarkers, such as telomere length, senescence markers, and DNA methylation, suggest that biological aging is accelerated in people with MS compared with age- and sex-matched healthy controls. Furthermore, distinguishing biological age from chronological may afford more precision in determining aging effects in MS. Here we review the current literature on aging biology and its impact on MS pathogenesis. Future research on this topic may lead to the development of novel biomarkers and senotherapy agents that slow neurological decline in people with progressive MS by targeting relevant aging-related pathways. </jats:p>

<jats:sec><jats:title>Background:</jats:title><jats:p> Multiple sclerosis misdiagnosis remains a problem despite the well-validated McDonald 2017. For proper evaluation of errors in the diagnostic process that lead to misdiagnosis, it is adequate to incorporate patients who are already under regular follow-up at reference centers of demyelinating diseases. </jats:p></jats:sec><jats:sec><jats:title>Objectives:</jats:title><jats:p> To evaluate multiple sclerosis misdiagnosis in patients who are on follow-up at a reference center of demyelinating diseases in Brazil. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> We designed an observational study including patients in regular follow-up, who were diagnosed with multiple sclerosis at our specialized outpatient clinic in the Hospital of Clinics in the University of Sao Paulo, from 1996 to 2021, and were reassessed for misdiagnosis in 2022. We evaluated demographic information, clinical profile, and complementary exams and classified participants as “established multiple sclerosis,” “non-multiple sclerosis, diagnosed,” and “non-multiple sclerosis, undiagnosed.” Failures in the diagnostic process were assessed by the modified Diagnostic Error Evaluation and Research tool. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> A total of 201 patients were included. After analysis, 191/201 (95.02%) participants were confirmed as “established multiple sclerosis,” 5/201 (2.49%) were defined as “non-multiple sclerosis, diagnosed,” and 5/201 (2.49%) were defined as “non-multiple sclerosis, undiagnosed.” </jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p> Multiple sclerosis misdiagnosis persists in reference centers, emphasizing the need for careful interpretation of clinical findings to prevent errors. </jats:p></jats:sec>

<jats:sec><jats:title>Background:</jats:title><jats:p> Neuromyelitis optic spectrum disorder (NMOSD) is a rare demyelinating, autoimmune disease and the burden in United States is not well characterized. </jats:p></jats:sec><jats:sec><jats:title>Objective:</jats:title><jats:p> The objective of this study was to determine the 2022 US prevalence of NMOSD. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> We constructed a cross-sectional study using aggregated electronic health record data for 25.7 million patients who had a 2022 clinical encounter. The data originated from the TriNetX US Collaborative Network of 55 healthcare organizations that span all 50 states. NMOSD prevalence was determined by querying for age-interval, sex, and race combinations, with direct standardization to the 2022 US Census data. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> There were 1772 NMOSD patients among 25,743,039 patients for a prevalence of 6.88/100,000. Prevalence was the highest in Blacks (12.99/100,000) who represented 27.7% of NMOSD patients, then Asians (9.41/100,000and Whites (5.58/100,000). Among females, the prevalence of NMOSD was 9.48/100,000, and Black and Asian females had a 2.65- and 1.94-times higher prevalence than White females. In males, the prevalence of NMOSD was 3.52/100,000 and it did not differ by race. We observed a 3/5:1 female-to-male ratio in NMOSD. The age- and sex-adjusted 2022 estimate of persons with NMOSD in the United States was 15,413 females and 6233 males. </jats:p></jats:sec><jats:sec><jats:title>Conclusion:</jats:title><jats:p> We estimate that there were near 22,000 Americans living with NMOSD in 2022. </jats:p></jats:sec>

<jats:sec><jats:title>Background:</jats:title><jats:p> Comparisons between cladribine and other potent immunotherapies for multiple sclerosis (MS) are lacking. </jats:p></jats:sec><jats:sec><jats:title>Objectives:</jats:title><jats:p> To compare the effectiveness of cladribine against fingolimod, natalizumab, ocrelizumab and alemtuzumab in relapsing-remitting MS. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> Patients with relapsing-remitting MS treated with cladribine, fingolimod, natalizumab, ocrelizumab or alemtuzumab were identified in the global MSBase cohort and two additional UK centres. Patients were followed for ⩾6/12 and had ⩾3 in-person disability assessments. Patients were matched using propensity score. Four pairwise analyses compared annualised relapse rates (ARRs) and disability outcomes. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> The eligible cohorts consisted of 853 (fingolimod), 464 (natalizumab), 1131 (ocrelizumab), 123 (alemtuzumab) or 493 (cladribine) patients. Cladribine was associated with a lower ARR than fingolimod (0.07 vs. 0.12, p = 0.006) and a higher ARR than natalizumab (0.10 vs. 0.06, p = 0.03), ocrelizumab (0.09 vs. 0.05, p = 0.008) and alemtuzumab (0.17 vs. 0.04, p &lt; 0.001). Compared to cladribine, the risk of disability worsening did not differ in patients treated with fingolimod (hazard ratio (HR) 1.08, 95% confidence interval (CI) 0.47–2.47) or alemtuzumab (HR 0.73, 95% CI 0.26–2.07), but was lower for patients treated with natalizumab (HR 0.35, 95% CI 0.13–0.94) and ocrelizumab (HR 0.45, 95% CI 0.26–0.78). There was no evidence for a difference in disability improvement. </jats:p></jats:sec><jats:sec><jats:title>Conclusion:</jats:title><jats:p> Cladribine is an effective therapy that can be viewed as a step up in effectiveness from fingolimod, but is less effective than the most potent intravenous MS therapies. </jats:p></jats:sec>

<jats:sec><jats:title>Background:</jats:title><jats:p> Multiple sclerosis (MS) prevalence is increasing globally. </jats:p></jats:sec><jats:sec><jats:title>Objectives:</jats:title><jats:p> To determine whether increased prevalence is continuing within Australia using our validated prescription-based ascertainment method. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> We used methods employed in our 2010 and 2017 prevalence estimates. Disease-modifying therapy (DMT) prescriptions were extracted from Australia’s Pharmaceutical Benefits Scheme data for January–December 2021. DMT penetrance was calculated using data from the Australian MS Longitudinal Study. We divided the total number of monthly prescriptions by 12 or 2 (except alemtuzumab), adjusted for DMT penetrance and Australian population estimates. Prevalences in Australian states/territories were age-standardised. 2021 prevalence estimates were compared with 2010 and 2017 prevalence estimates using Poisson regression. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> Number of people with MS in Australia in 2021 was 33,335; an increase of 7728 from 2017 (30.2%) and 12,092 from 2010 (56.6%) and increasing at a faster rate than population change (+10.1%, +14.1%). Age-standardised prevalence was 136.1/100,000 (increased from 103.7/100,000 in 2017). The previously demonstrated positive latitudinal gradient in 2010 and 2017 persisted in 2021, with Tasmania (southernmost state) having the highest prevalence (age-standardised: 203.5/100,000) while northernmost states had the lowest. </jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p> In line with global trends, MS prevalence is escalating in Australia, particularly in higher-latitude states. MS prevention is crucial to halt this disturbing trend. </jats:p></jats:sec>