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Abstract Background We investigated if global gene expression and transcription networks in B-lymphocytes of siblings with multiple sclerosis (MS) were different from healthy siblings. Results Using virus-transformed immortalized B cells and human whole genome bioarrays with validation using RT-qPCR, we found that in siblings with MS, genes for CXCL10, serpin B1 and FUT4 were up regulated whereas CDC5L, TNFRSF19 and HLA-DR were down regulated, among others; transcription analysis showed two intersecting clusters of transcriptional factors - the larger, governed by the upregulated transcription factor 2 (TCF2) and the smaller network regulated by the downregulated CDC5L. Conclusion No study has linked TCF2 to MS and to better understand the role of TCF2 in MS, studies in larger cohorts are required.

Abstract Background To our knowledge, no study to date has investigated the prescribing patterns of immunomodulatory agents (IMAs) in an outpatient setting in the United States. To address this issue, we performed retrospective data analyses on National Ambulatory Medical Care Survey (NAMCS) data for MS patient visits between 1998 and 2004. Methods NAMCS data are a weighted estimate of the nationwide frequency of patients' outpatient clinic visits. We analyzed NAMCS data in the following categories: (1) the proportion of MS patient visits to neurologists, family practitioners or internists, (2) age/gender/race/geographical distribution patterns in patient visits, and (3) the proportion of patients on IMA treatment among established MS patients. Results There were an estimated 6.7 million multiple sclerosis (MS) patient visits to the clinics between 1998–2004. Neurologists recorded the most patient visits, 50.7%. Patient visits were mostly in the fourth and fifth decade age group (57.9%). The male to female ratio was 1:4. No statistical evidence was observed for a decline or increase in IMA usage. About 62% patients visiting neurologists and 92% seen by family practitioners/internists were not using IMAs. Our results suggest that between the years 1998–2003, the use of interferon-1a tended to decline while the use of interferon-1b and glatiramer acetate, increased. Conclusion Strategies that lead to improved use of IMAs in the management of MS in the outpatient setting are needed.

Background: Previous epidemiologic studies of autoimmune diseases in the United States (US) have included a limited number of diseases or used meta-analyses that rely on different data collection methods and analyses for each disease., Methods: To estimate the prevalence of autoimmune diseases in the US, we used electronic health record data from six large medical systems in the US. We developed a software program using common methodology to compute the estimated prevalence of autoimmune diseases alone and in aggregate that can be readily used by other investigators to replicate or modify the analysis over time., Results: Our findings indicate that over 15 million people, or 4.6% of the US population, have been diagnosed with at least one autoimmune disease from January 1, 2011, to June 1, 2022, and 34% of those are diagnosed with more than one autoimmune disease. As expected, females (63% of those with autoimmune disease) were almost twice as likely as males to be diagnosed with an autoimmune disease. We identified the top 20 autoimmune diseases based on prevalence and according to sex and age., Conclusion: Thus, we provide, for the first time, a large-scale prevalence estimate of autoimmune disease in the US by sex and age., Funding: Autoimmune Registry Inc., the National Heart Lung and Blood Institute, the National Center for Advancing Translational Sciences, the Intramural Research Program of the National Institute of Environmental Health Sciences.

No study has investigated the length of time it takes to diagnose multiple sclerosis (MS) or neuromyelitis optic spectrum disorder (NMOSD, aquaporin 4 antibody disease or myelin oligodendrocyte glycoprotein antibody disease, MOGAD) following the onset of de novo optic neuritis (ON). Minimizing the time between ON and downstream diagnoses needs urgency since early diagnosis equals early treatment. The time elapsed from ON to a subsequent diagnosis of MS/NMOSD was estimated through analysis of retrospective data collected from the Axon Registry (AR) of the American Academy of Neurology (AAN) and from the University of Kentucky (UK), Lexington. The time to diagnose MS/NMOSD was arbitrarily set as occurring < 6 months (early) or > 6 months (delayed) following ON. Data was collected between 2007 and 2021 (AR) and 2012 to 2022, for UK, respectively. Of the 4015 ON patients from the AR dataset, 1069 (26.6 %) were diagnosed with MS, with 857 (80.2 %) diagnosed < 6 months (early) and 212 (19.8 %) diagnosed after > 6 months (delayed). Secondly, 420/4015 (10.4 %) were diagnosed with NMOSD (either MOGAD or AQP4 antibody disease), of which 340/420 (80.9 %) were diagnosed < 6 months (early) and 80/420 (19 %) diagnosed > 6 months (delayed). In the UK dataset, a total of 90/1464 individuals (6.14 %) were diagnosed with MS; of these, 69 patients (76.7 %) were diagnosed at < 6 months (early) and included a sub-group of 25 (27.8 %) diagnosed < 4 weeks; 21 (23.3 %) were diagnosed > 6 months (delayed) following ON. In either dataset (AR or UK, between 20 % - 23 % of MS diagnoses occurred > 6 months (delayed) after a diagnosis of ON. An accelerated diagnosis (4 weeks or less) of MS/NMOSD following ON in the UK data suggests that it is possible to minimize the time to a downstream diagnosis if a 'test bundle' of MRI of orbits, brain, C-spine, cerebrospinal fluid (CSF) analysis, and serum testing for NMOSD is used. Additional studies using prospective, larger datasets are required to confirm our findings., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Alterations to cilia are responsible for a wide range of severe disease; however, understanding of the transcriptional control of ciliogenesis remains incomplete. In this study we investigated whether altered cilia-mediated signaling contributes to the pleiotropic phenotypes caused by the Forkhead transcription factor FOXC1. Here, we show that patients with FOXC1-attributable Axenfeld-Rieger Syndrome (ARS) have a prevalence of ciliopathy-associated phenotypes comparable to syndromic ciliopathies. We demonstrate that altering the level of Foxc1 protein, via shRNA mediated inhibition, CRISPR/Cas9 mutagenesis and overexpression, modifies cilia length in vitro. These structural changes were associated with substantially perturbed cilia-dependent signaling [Hedgehog (Hh) and PDGFRα], and altered ciliary compartmentalization of the Hh pathway transcription factor, Gli2. Consistent with these data, in primary cultures of murine embryonic meninges, cilia length was significantly reduced in heterozygous and homozygous Foxc1 mutants compared to controls. Meningeal expression of the core Hh signaling components Gli1, Gli3 and Sufu was dysregulated, with comparable dysregulation of Pdgfrα signaling evident from significantly altered Pdgfrα and phosphorylated Pdgfrα expression. On the basis of these clinical and experimental findings, we propose a model that altered cilia-mediated signaling contributes to some FOXC1-induced phenotypes., (© 2024. The Author(s).)

Data on minority group physicians from diverse racial/ethnic backgrounds is sparse and not reported by PG metrics at the national level. While PG metrics typically concentrate on the individual, patterns and trends are clearly discernible at the group level and comparison of groups to capture patterns may yield results hitherto unknown. One could even envisage using AI to capture any trends, differences, and comparative figures to build databases for the future. It is time to retool PG surveys to fit the modern U.S. healthcare workforce and be inclusive, and not selective at the individual level.

The incidence of new-onset seizures, which we defined as de novo seizures occurring within 4 weeks of receiving any of the US Food and Drug Administration-approved COVID-19 vaccinations as reported in patient-reported data compiled in the US Centers for Disease Control and Prevention Vaccine Adverse Events Reporting System Data (CDC VAERS), has not been explored. The VAERS database contains de-identified patient-reported adverse events following vaccination and represents post-marketing surveillance and analysis of vaccine safety. After adjusting for time at risk, this resulted in estimated incidence rates of 3.19 seizures per 100 000 persons per year for the COVID-19 vaccine and 0.090 seizures per 100 000 persons per year for the influenza vaccines. A data-driven, individualized dataset that is comprehensive and coupled with a longitudinal follow-up in larger numbers of vaccinated individuals is needed to expand on our preliminary findings of vaccine-related seizures., (© 2022 British Pharmacological Society.)

Objective: We investigated if anti-tumor necrosis factor-α (anti-TNF-α) drugs used in the treatment of inflammatory bowel disease (IBD) alter the incidence of MS and if so, to understand the magnitude of such an effect., Methods: This is a retrospective cohort study of data from Truven Health Market Scan administrative claims database. The patients included in the study had to be ≥ 18 years of age. The presence of IBD was based on at least 2 claims of International Classification of Diseases (ICD-9 or 10) diagnosis codes. The IBD diagnosis index date had to precede the MS diagnosis index date for inclusion in the study. The diagnosis of multiple sclerosis (MS) was defined as having at least 2 claims for the disease (ICD 9, 340 and ICD 10 codes, G35) and at least one prescription claim for any of the drugs that were defined as MS therapy., Results: Patients with IBD had 1.32 times the risk of MS incidence compared to healthy controls (adjusted incidence rate ratio (IRR): 1.32; 95% CI: 1.03 - 1.71; p = .0312). Patients with IBD exposed to anti-TNF-α therapies had a 43% increase in the incidence of MS compared to those with IBD without exposure (adjusted incidence rate: 1.43; 95% CI: .062 - 3.32; p = .3989). Among CD patients treated anti-TNF-α medications an increase in the incidence of MS, compared to CD patients not exposed to such medications was observed (IRR = 2.62; 95% CI: 1.00 to 6.83; p = 0.049), statistically significant. After adjusting for age/gender, patients with CD using anti-TNF-α agents had an increase of incidence in MS (adjusted IRR: 2.24; 95% CI: 0.85 - 5.94; p = .1035) but it was not statistically significant., Conclusions: Use of anti-TNF-α drugs in CD was associated with a statistically significant increase in the incidence of MS but this effect was lost when controlled for age/gender., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest.

Aquaporin 4 antibody (anti-AQP4) positive neuromyelitis optica spectrum disorder (NMOSD) is known to occur in the setting of myasthenia gravis (MG). However, comorbid MG with myelin oligodendrocyte glycoprotein antibody (anti-MOG) positive NMOSD has not been reported. We present a case of anti-MOG and anti-AQP4 positive NMOSD in a patient with long-standing MG. The patient presented with acute right-sided weakness with MRI demonstrating extensive spinal cord edema extending from T2 to the medulla with associated contrast enhancement. To our knowledge, this is the first reported case of anti-MOG and anti-AQP4 positive NMOSD in a patient with known MG., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The symptoms of multiple sclerosis (MS) can overlap with neuromyelitis optica spectrum disorder (NMOSD). Although testing is available for aquaporin 4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies, screening for NMOSD is recommended but not mandatory to establish a diagnosis of MS., Methods and Results: We queried 319,994 individuals who filed claims for MS and NMOSD in a Truven Health Analytics (THA) database and had at least one year of uninterrupted health insurance coverage. Of this cohort, 2001 (0.62%) were diagnosed as having NMOSD after an initial diagnosis of MS, based on ICD 9/10 codes. Since THA only offers claims-based data, we initiated an individual patient-based data search at our medical center to screen for potential misdiagnoses. We identified 4/54 (7.4%) NMOSD cases that were initially diagnosed as having MS., Conclusions: The results from our small study have significant implications--symptoms, clinical presentation or classic radiological findings perhaps cannot reliably separate MS from NMOSD. If our study findings can be replicated, guidelines to diagnose MS ought to recommend that NMOSD be excluded first despite typical clinical and radiological findings pointing to MS., Competing Interests: Declaration of Competing Interest The authors report no funding and have no disclosures., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Even with increasing data implicating the venous side of the vascular tree of the brain in MS, no diagnostic or treatment protocol has addressed the risk of acute stroke in MS and no systematic study has documented the incidence or prevalence of acute strokein MS patients. Approximately 795,000 strokes occur in the U.S. each year-every 40 s, someone has a stroke and every 4 min, a person dies from a stroke. However, no large, prospective, multi-center study has investigated acute stroke incidence in MS patients either in the U.S. or internationally, leaving a gap in our understanding of the association between stroke and MS. Additionally, data on acute stroke in MS as determined by age, gender or ethnicity are unknown. To compound this further, the diagnosis and definition of acute stroke in MS remains poorly understood. A survey of published literature shows a few anecdotal reports of acute stroke occurring among MS patients, but most studies do not address the fundamental association between acute stroke and MS. Symptoms of acute stroke and MS can overlap and the lack of clear clinical/radiological criteria that alert the patient or clinician to the development of acute stroke in an MS patient compound the dilemma, even leading to the administration of IV alteplase in cases that are later diagnosed as either MS or having an "MS flare." Clinical trials that use aspirin in multiple sclerosis are urgently needed.

The US Food and Drug Administration (FDA) approved Zinbryta, an interleukin-2 receptor blocking antibody (daclizumab; Biogen and AbbVie) for the treatment of adults with relapsing forms of multiple sclerosis (MS) in May, 2016. It was also approved by the European Union in July, 2016. Zinbryta is a long-acting, self-administered monthly injection that was branded as a new MS drug for patients who needed a "new option for treatment." It blocks interleukin-2 receptor alpha (CD25) and modulates T-cell expansion. The drug was withdrawn from the market in March, 2018 following 12 reports from Germany (9), United States (2), and Spain (1) following the development of "inflammatory encephalitis and meningoencephalitis" in patients on Zinbryta. Although cases of hepatotoxicity made news with Zinbryta earlier along this drug's postmarketing journey in the treatment of patients with MS, the European Medicines Agency (EMA) ordered a review of the risks of hepatotoxicity with Zinbryta use June, 2017; this analysis will focus on the pharmacovigilance data concerning the central nervous system (CNS) complications. The details of the CNS complications have been elucidated by EMA. Every drug failure provides an opportunity for learning, but it is also noteworthy that no FDA-approved MS drug in modern times has met with such an untimely, sudden, and inglorious exit. This should serve as a cautionary tale for all clinicians who use "newer MS drugs" that have mushroomed in recent memory following a flurry of recent FDA approvals., Competing Interests: Declaration of Conflicting Interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Anti-CD 20 therapies have found significant uses in multiple sclerosis (MS). Based singularly on the accumulated evidence with the use of rituximab (RTX; Rituxan, Genentech, and Biogen) in neuroimmunological diseases, ocrelizumab (OCR; Ocrevus, Genentech) was developed as a treatment option for MS and selectively targets CD20 B cells, a cell surface antigen found on pre-B cells, mature, and memory B cells, but not on lymphoid stem cells and plasma cells. On the basis of indirect evidence, elimination of the antigen-presenting capabilities and antigen nonspecific immune functions of B cells appear to be central to the therapeutic efficacy of anti-CD20 B-cell therapies. An important question is this-Why does the drug need to be dosed at fixed intervals and not based on a measurable endpoint, such as tracking peripheral CD20 cell counts? There is minimal scientific validity in infusing the drug every 6 months particularly if CD20 cell counts are negligible in the peripheral blood. In this analysis, a case is made for following CD19 cell populations as a surrogate for CD20 cells on a monthly basis to guide OCR redosing parameters and does not follow a scheduled dosing parameter., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.