Predictors of a relapsing course in myelin oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described demyelinating disorder, and children represent about 50% of all cases. Almost half of the patients experience relapses, but very few studies have evaluated predictors of relapse risk, challenging clinical management. The study aimed to identify predictors at MOGAD onset that are associated with a relapsing course. METHODS: Prospectively collected data from paediatric patients with MOGAD seen by the US Network of Paediatric MS Centres were leveraged. Univariable and adjusted multivariable models were used to predict recurrent disease. RESULTS: We identified 326 MOGAD cases (mean age at first event 8.9 years [SD 4.3], 57% female, 77% white and 74% non-Hispanic) and 46% relapsed during a mean follow-up of 3.9 years (SD 4.1). In the adjusted multivariable model, female sex (HR 1.66, 95% CI 1.17 to 2.36, p=0.004) and Hispanic/Latino ethnicity (HR 1.77, 95% CI 1.19 to 2.64, p=0.005) were associated with a higher risk of relapsing MOGAD. Maintenance treatment initiated before a second event with rituximab (HR 0.25, 95% CI 0.07 to 0.92, p=0.037) or intravenous immunoglobulin (IVIG) (HR 0.35, 95% CI 0.14 to 0.88, p=0.026) was associated with lower risk of a second event in multivariable analyses. Conversely, maintenance steroids were associated with a higher estimated relapse risk (HR 1.76, 95% CI 0.90 to 3.45, p=0.097). CONCLUSION: Sex and ethnicity are associated with relapsing MOGAD. Use of rituximab or IVIG therapy shortly after onset is associated with a lower risk of the second event. Preventive treatment after a first event could be considered for those with a higher relapse risk.

Clinical and magnetic resonance imaging outcomes in pediatric-onset MS patients on fingolimod and ocrelizumab.

BACKGROUND: Observational studies looking at clinical a++nd MRI outcomes of treatments in pediatric MS, could assess current treatment algorithms, and provide insights for designing future clinical trials. OBJECTIVE: To describe baseline characteristics and clinical and MRI outcomes in MS patients initiating ocrelizumab and fingolimod under 18 years of age. METHODS: MS patients seen at 12 centers of US Network of Pediatric MS were included in this study if they had clinical and MRI follow-up and started treatment with either ocrelizumab or fingolimod prior to the age of 18. RESULTS: Eighty-seven patients initiating fingolimod and 52 initiating ocrelizumab met the inclusion criteria. Before starting fingolimod, mean annualized relapse rate was 0.43 (95 % CI: 0.29 - 0.65) and 78 % developed new T2 lesions while during treatment it was 0.12 (95 % CI: 0.08 - 1.9) and 47 % developed new T2 lesions. In the ocrelizumab group, the mean annualized relapse rate prior to initiation of treatment was 0.64 (95 % CI: 0.38-1.09) and a total of 83 % of patients developed new T2 lesions while during treatment it was 0.09 (95 % CI: 0.04-0.21) and none developed new T2 lesions. CONCLUSION: This study highlights the importance of evaluating current treatment methods and provides insights about the agents in the ongoing phase III trial comparing fingolimod and ocrelizumab.

Gene-environment interactions: Epstein-Barr virus infection and risk of pediatric-onset multiple sclerosis.

BACKGROUND AND OBJECTIVE: Prior Epstein-Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS. METHODS: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother's education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs). RESULTS: A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p < 0.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI = 10.25, 95% confidence interval (CI) = 3.78 to 16.72; AP = 0.61, 95% CI = 0.47 to 0.75). There was evidence for multiplicative interaction (p < 0.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR) = 3.43, 95% CI = 1.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction (p = 0.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP = 0.30, 95% CI = 0.03 to 0.58). CONCLUSION: We report evidence for interactions between childhood EBV infection and DRB1*15 and the GG genotype of CD86 POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk.

Gene-environment interactions and risk of pediatric-onset multiple sclerosis associated with time spent outdoors.

BACKGROUND: Our previous study identified a significant association between lower time spent outdoors, as a proxy of sun exposure, and a higher risk of pediatric-onset multiple sclerosis (POMS). UV radiation modulates the expression of several genes, but it is unknown whether these genes modify the effect of sun exposure on POMS risk. METHODS: In an age- and sex-matched case-control study, we evaluated the additive and multiplicative interactions between time spent outdoors and genetic non-HLA risk variants for developing POMS within the metabolic pathways of UV radiation, including CD28(rs6435203), CD86(rs9282641), and NFkB1(rs7665090) and the top two HLA risk factors (presence of DRB1×15 and absence of A*02). RESULTS: In an adjusted model (332 POMS cases, 534 healthy controls), greater time compared to <30 min/day spent outdoors during the prior summer and higher UV radiation dose were associated with decreased odds of POMS (OR 0.66, 95% CI 0.56-0.78, p < 0.001; OR 0.78, 95 % CI 0.62-0.98, p = 0.04, respectively). No significant additive or multiplicative interactions were found between risk factors. CONCLUSIONS: The exploration of gene-environment interactions in the risk of developing MS can unravel the underlying mechanisms involved. Although we do not have evidence that our candidate genes contribute to interactions, other genes may.

Demographic Features and Clinical Course of Patients With Pediatric-Onset Multiple Sclerosis on Newer Disease-Modifying Treatments.

BACKGROUND: Treatment of pediatric-onset multiple sclerosis (POMS) is challenging given the lack of safety and efficacy data in the pediatric population for many of the disease-modifying treatments (DMTs) approved for use in adults with MS. Our objective was to describe the demographic features and clinical and radiologic course of patients with POMS treated with the commonly used newer DMTs within the US Network of Pediatric MS Centers (NPMSC). METHODS: This is an analysis of prospectively collected data from patients who initiated treatment before age 18 with the DMTs listed below at the 12 regional pediatric MS referral centers participating in the NPMSC. RESULTS: One hundred sixty-eight patients on dimethyl fumarate, 96 on fingolimod, 151 on natalizumab, 166 on rituximab, and 37 on ocrelizumab met criteria for analysis. Mean age at DMT initiation ranged from 15.2 to 16.5 years. Disease duration at the time of initiation of index DMT ranged from 1.1 to 1.6 years with treatment duration of 0.9-2.0 years. Mean annualized relapse rate (ARR) in the year prior to initiating index DMT ranged from 0.4 to 1.0. Mean ARR while on index DMT ranged from 0.05 to 0.20. New T2 and enhancing lesions occurred in 75%-88% and 55%-73% of the patients, respectively, during the year prior to initiating index DMT. After initiating index DMT, new T2 and enhancing lesions occurred in 0%-46% and 11%-34% patients, respectively. Rates of NEDA-2 (no evidence of disease activity) ranged from 76% to 91% at 6 months of treatment with index DMTs and 66% to 84% at 12 months of treatment with index DMTs. CONCLUSIONS: Though limited by relatively short treatment duration with the index DMTs, our data suggest clinical and MRI benefit, as well as high rates of NEDA-2, in a large number of POMS patients, which can be used to guide future studies in this population.

Reproductive issues and multiple sclerosis: 20 questions.

Multiple sclerosis (MS) is commonly diagnosed in young adults during their reproductive years. Consequently, concerns about family planning and MS management related to pregnancy and breastfeeding are often encountered in clinical practice. Pregnancy itself is not harmful for women with MS. However, disease-modifying therapies (DMTs) have implications for reproductive planning, including stopping treatment while trying to conceive and during pregnancy, as well as managing fetal risks. People with MS and their care team must engage in collaborative decision-making before, during, and after pregnancy. Based on the results of a consensus-building initiative, answers are provided to 20 frequently asked questions regarding the management of MS during pregnancy planning, pregnancy, and the postpartum period.

Pearls & Oy-sters: Hemorrhagic Myelitis Following SARS-CoV-2 Infection.

Hemorrhage in the setting of myelitis is rarely seen in clinical practice. We report a series of 3 women aged 26, 43, and 44 years, who presented with acute hemorrhagic myelitis within 4 weeks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Two required intensive care, and 1 had severe disease with multiorgan failure. Serial MRI of the spine demonstrated T2-weighted hyperintensity with T1-weighted postcontrast enhancement in the medulla and cervical spine (patient 1) and thoracic spine (patients 2 and 3). Hemorrhage was identified on precontrast T1-weighted, susceptibility-weighted, and gradient echo sequences. Distinct from typical inflammatory or demyelinating myelitis, clinical recovery was poor in all cases, with residual quadriplegia or paraplegia, despite immunosuppression. These cases highlight that although hemorrhagic myelitis is rare, it can occur as a post/parainfectious complication of SARS-CoV-2 infection.

Characteristics of pediatric patients with multiple sclerosis and related disorders infected with SARS-CoV-2.

BACKGROUND: Pediatric patients with multiple sclerosis (POMS) and related disorders, clinically isolated syndrome (CIS), myelin oligodendrocyte glycoprotein antibody disorder (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD), are commonly treated with immunosuppressants. Understanding the impact of SARS-CoV-2 infection in patients may inform treatment decisions. OBJECTIVE: Characterize SARS-CoV-2 infection prevalence and severity among a cohort of patients with POMS and related disorders, as well as the impact of disease-modifying therapies (DMTs). METHODS: POMS and related disorders patients enrolled in a large, prospective registry were screened for COVID-19 during standard-of-care neurology visits. If confirmed positive of having infection, further analysis was undertaken. RESULTS: Six hundred and sixty-nine patients were surveyed between March 2020 and August 2021. There were 73 confirmed COVID-19 infections. Eight of nine hospitalized patients (89%), and all patients admitted to the ICU were treated with B cell depleting therapy. The unadjusted odds ratio of hospitalization among those who tested positive of having had COVID-19 was 15.27 among those on B-cell-depleting therapy (p = 0.016). CONCLUSIONS: B-cell-depleting treatment was associated with a higher risk of COVID-19, higher rates of hospitalization, and ICU admission, suggesting this therapy carries a higher risk of severe infection in POMS and related disorders.

Silent findings: Examination of asymptomatic demyelination in a pediatric US cohort.

BACKGROUND AND OBJECTIVES: Limited data is available on children with evidence of silent central nervous system demyelination on MRI. We sought to characterize the population in a US cohort and identify predictors of clinical and radiologic outcomes. METHODS: We identified 56 patients such patients who presented with incidental MRI findings suspect for demyelination, enrolled through our US Network of Pediatric Multiple Sclerosis Centers, and conducted a retrospective review of 38 patients with MR images, and examined risk factors for development of first clinical event or new MRI activity. MRI were rated based on published MS and radiologically isolated syndrome (RIS) imaging diagnostic criteria. RESULTS: One-third had a clinical attack and ¾ developed new MRI activity over a mean follow-up time of 3.7 years. Individuals in our cohort shared similar demographics to those with clinically definite pediatric-onset MS. We show that sex, presence of infratentorial lesions, T1 hypointense lesions, juxtacortical lesion count, and callosal lesions were predictors of disease progression. Interestingly, the presence of T1 hypointense and infratentorial lesions typically associated with worse outcomes were instead predictive of delayed disease progression on imaging in subgroup analysis. Additionally, currently utilized diagnostic criteria (both McDonald 2017 and RIS criteria) did not provide statistically significant benefit in risk stratification. CONCLUSION: Our findings underscore the need for further study to determine if criteria currently used for pediatric patients with purely radiographic evidence of demyelination are sufficient.

Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis.

BACKGROUND: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown. OBJECTIVE: To test whether genes harboring rare variants associated with adult-onset MS risk (PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS. METHODS: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method "SKAT-O," we tested the association between candidate genes and POMS risk. RESULTS: After correction for multiple comparisons, one adult-onset MS gene (PRF1, p = 2.70 × 10-3) and two MHC genes (BRD2, p = 5.89 × 10-5 and AGER, p = 7.96 × 10-5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501. CONCLUSION: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.

Gene-environment interactions increase the risk of paediatric-onset multiple sclerosis associated with household chemical exposures.

BACKGROUND: We previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis. METHODS: Using a case-control paediatric multiple sclerosis study, gene-environment interaction between exposure to household chemicals and genotypes for risk of paediatric-onset multiple sclerosis was estimated.Genetic risk factors of interest included the two major HLA multiple sclerosis risk factors, the presence of DRB1*15 and the absence of A*02, and multiple sclerosis risk variants within the metabolic pathways of common household toxic chemicals, including IL-6 (rs2069852), BCL-2 (rs2187163) and NFKB1 (rs7665090). RESULTS: 490 paediatric-onset multiple sclerosis cases and 716 controls were included in the analyses. Exposures to insect repellent for ticks or mosquitos (OR 1.47, 95% CI 1.06 to 2.04, p=0.019), weed control products (OR 2.15, 95% CI 1.51 to 3.07, p<0.001) and plant/tree insect or disease control products (OR 3.25, 95% CI 1.92 to 5.49, p<0.001) were associated with increased odds of paediatric-onset multiple sclerosis. There was significant additive interaction between exposure to weed control products and NFKB1 SNP GG (attributable proportions (AP) 0.48, 95% CI 0.10 to 0.87), and exposure to plant or disease control products and absence of HLA-A*02 (AP 0.56; 95% CI 0.03 to 1.08). There was a multiplicative interaction between exposure to weed control products and NFKB1 SNP GG genotype (OR 2.30, 95% CI 1.00 to 5.30) but not for other exposures and risk variants. No interactions were found with IL-6 and BCL-2 SNP GG genotypes. CONCLUSIONS: The presence of gene-environment interactions with household toxins supports their possible causal role in paediatric-onset multiple sclerosis.

Leadership Inequity, Burnout, and Lower Engagement of Women in Medicine.

Gender parity has been reached in graduation rates from medical school, yet women in medicine continue to face obstacles in promotion, compensation and opportunities, leading to leadership inequity, higher burnout and lower engagement. These complex issues with gender are just one aspect of the wide challenges related to diversity, equity and inclusion among medical professionals. While there are no "one size fits all" approaches, psychologists are well positioned to lead efforts related to promoting leadership equity, reducing burnout and raising engagement because of their training in communication skills, programmatic development and empathetic listening. This paper details several evidence-based efforts in which psychologists can lead in these ongoing issues for women in medicine.

MOG and AQP4 Antibodies among Children with Multiple Sclerosis and Controls.

OBJECTIVE: The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among patients with pediatric-onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG-IgG-associated disease (MOGAD), and identify clinical features associated with final diagnosis. METHODS: Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case-control study on POMS risk factors. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays. RESULTS: AQP4-IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG-IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty-five of 30 patients positive with MOG-IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re-review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein-Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001). INTERPRETATION: MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4-IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2023;93:271-284.

Gender Representation Among Physician Authors of Practice Guidelines Developed, Endorsed, or Affirmed by the American Academy of Neurology.

BACKGROUND AND OBJECTIVES: To assess American Academy of Neurology (AAN)-recommended Practice Guidelines (PGs) for equity in gender representation among physician authors. METHODS: This cross-sectional study included AAN-recommended PG publications from January 1, 2015, to December 31, 2020. Author degrees and gender were identified by 2 reviewers using the publication and/or online searches. Gender was determined from pronouns or photographs. Gender representation was compared with Association of American Medical Colleges (AAMC) data on academic neurologists. Data were analyzed using Z tests of 2 proportions and descriptive statistics. RESULTS: AAMC benchmarks report academic women neurologists represented 35% of the specialty in 2015, 38% in 2018, and 39% in 2020. We identified 68 unique PG publications with 709 physician authors, 31% (223) women, 68% (484) men, and 0.3% (2) gender could not be identified. Representation of women physicians was low among PG authors across all benchmarks, significantly so for 2018 and 2020 (p < 0.01). Among physician first authors, women were significantly underrepresented across all benchmarks (18% [12/65], p < 0.01). Representation of women physicians was lower when men physicians were first authors vs women physicians (31% [161/524] vs 43% [50/118], p = 0.02). Among subspecialties with 10+ PGs, women physician authorship was highest in child neurology (48% [57/120]) and lowest in stroke and vascular neurology (16% [18/113]). DISCUSSION: We found that women physicians were underrepresented as authors of AAN-recommended PGs. This suggests a missed opportunity for neurology because PGs that include expertise from women physicians may improve care and translation into practice. In addition, women physicians lose out on professional development from authorship. Further research is needed to understand causality and address gaps.

Therapeutic Response in Pediatric Neuromyelitis Optica Spectrum Disorder.

BACKGROUND AND OBJECTIVE: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition, which can lead to significant disability, and up to 3%-5% of the cases have a pediatric onset. There are limited studies to guide physicians in disease-modifying treatment (DMT) choices for children with NMOSD. METHODS: This retrospective cohort study evaluated children with NMOSD cases followed at 12 clinics in the US Network of Pediatric MS Centers. Cases were classified as aquaporin-4 antibody positive (AQP4+) and double seronegative (DS) when negative for AQP4+ and for myelin oligodendrocyte glycoprotein (MOG) antibody. The effect of initial DMTs including rituximab, mycophenolate, azathioprine, and IV immunoglobulin (IVIg) on the annualized relapse rate (ARR) was assessed by negative binomial regression. Time to disability progression (EDSS score increase ≥1.0 point) was modeled with a Cox proportional-hazards model. RESULTS: A total of 91 children with NMOSD were identified: 77 AQP4+ and 14 DS (85.7% females; 43.2% White and 46.6% African American). Eighty-one patients were started on a DMT, and 10 were treatment naive at the time of the analysis. The ARR calculated in all serogroups was 0.25 (95% CI 0.13-0.49) for rituximab, 0.33 (95% CI 0.19-0.58) for mycophenolate, 0.40 (95% CI 0.13-1.24) for azathioprine, and 0.54 (95% CI 0.28-1.04) for IVIg. The ARR in the AQP4+ subgroup was 0.28 (95% CI 0.14-0.55) for rituximab, 0.39 (95% CI 0.21-0.70) for mycophenolate, 0.41 (95% CI 0.13-1.29) for azathioprine, and 0.54 (95% CI 0.23-1.26) for IVIg. The ARR in the treatment-naive group was 0.97 (95% CI 0.58-1.60) in all serogroups and 0.91 (95% CI 0.53-1.56) in the AQP4+ subgroup. None of the initial DMT had a statistically significant effect on EDSS progression. DISCUSSION: The use of DMTs, particularly rituximab, is associated with a lowered annualized relapse rate in children with NMOSD AQP4+. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that use of disease-modifying treatments is associated with a lowered annualized relapse rate in children with NMOSD AQP4+.

A new look at cognitive functioning in pediatric MS.

OBJECTIVE: Cognitive involvement in pediatric multiple sclerosis (MS) relative to adult MS is less defined. This study advances our understanding by measuring cognitive performances in pediatric MS, adult MS, and pediatric healthy controls. METHODS: Consecutive relapsing pediatric MS participants from the United States Network of Pediatric MS Centers were compared with pediatric healthy controls and adults with relapsing MS. Participants were compared on two screening batteries: the Brief International Cognitive Assessment for MS and the Cogstate Brief Battery. Results were transformed to age-normative z scores. RESULTS: The pediatric groups (MS vs. Healthy Controls) did not differ on either battery's composite mean score or individual test scores (ps > 0.32), nor in the proportions impaired on either battery, Brief International Cognitive Assessment for MS (26% vs. 24%, p = 0.83); Cogstate Brief Battery (26% vs. 32%, p = 0.41). The pediatric versus adult MS group even after controlling for differences in disease duration performed better on the Brief International Cognition Assessment for MS composite (p = 0.03), Symbol Digit Modalities Test (p = 0.02), Rey Auditory Verbal Learning Test (p = 0.01), and Cogstate choice reaction time (p < 0.001). CONCLUSION: Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS.

Clinical Evaluation of Siponimod for the Treatment of Secondary Progressive Multiple Sclerosis: Pathophysiology, Efficacy, Safety, Patient Acceptability and Adherence.

Introduction: A number of disease-modifying therapies have been approved for use in relapsing-remitting multiple sclerosis (MS) in the past two decades. However, only few treatment options are available for patients with secondary progressive multiple sclerosis (SPMS). Siponimod has recently been approved for use in patients with active forms of SPMS (who experience clinical relapses or new lesions on MRI superimposed on secondary progression independent of relapse activity). Objective: The aim of this article is to provide a comprehensive review on the mechanism of action, efficacy, safety, cost effectiveness and patient adherence with siponimod. Methods: We performed a PubMed search using the search terms: "siponimod", "secondary progressive multiple sclerosis", "sphingosine 1-phosphate modulators". Titles and abstract were screened and selected for relevance to the key section of this article. Findings: Siponimod is an oral sphingosine-1-phosphate receptor (S1PR) modulator with selectivity to S1PR-1 and 5. Modulation of this receptor on lymphocytes causes its internalization and degradation, preventing their egress from lymphoid tissues to the blood. In the pivotal Phase 3 randomized controlled trial EXPAND, siponimod was superior to placebo in reducing the risk of disability progression confirmed at 3 and 6 months, as well as the development of new MRI lesions and the rate of brain volume loss. Secondary analysis also showed a benefit on measures of cognitive functioning. The risk of lymphopenia and first-dose bradycardia appears to be lower with siponimod compared to non-selective S1P1R modulators. Different CYP2C9 genotypes affect the metabolism of siponimod; hence, genetic testing is required to adapt the titration and final dose accordingly. Conclusion: Long-term extension and real-world studies will allow further evaluation of efficacy and safety in this population. Future research should focus on better defining SPMS, and identifying biomarkers of progression and outcome measures of treatment response in this category of patients.

Recommendations to Address the Unique Clinical and Psychological Needs of Transgender Persons Living With Multiple Sclerosis.

Background: People living with multiple sclerosis (MS) face challenges coping with chronic illnesses, and transgender (TGD) persons living with MS may experience additional unique challenges and barriers to care. Medical biases toward TGD people are widely reported, and best practices in TGD MS care have not been identified. Methods: A case report of a TGD person living with MS is reviewed that helped to identify and inform us regarding the unique aspects of their clinical and psychological care needs. We conducted a systematic review of the literature according to the standard methods in PubMed. The literature was reviewed and summarized for relevant topics related to the unique care needs of TGD persons living with MS, and proposed care recommendations were created. Results: We used the aforementioned case to identify and inform the special care needs and subsequently describe proposed recommendations to achieve inclusive comprehensive care of TGD persons with MS. The importance of providing an inclusive environment, comprehensive care, mental health screening, domestic violence screening, and case coordination are highlighted with the goal of providing best practice recommendations for the comprehensive inclusive care of TGD persons living with MS. Conclusions: The lack of published guidance on the care of TGD persons living with MS and our informative case have led to the proposed recommendations for the care of TGD persons living with MS.

Gene-environment interactions increase the risk of pediatric-onset multiple sclerosis associated with ozone pollution.

BACKGROUND: We previously reported a relationship between air pollutants and increased risk of pediatric-onset multiple sclerosis (POMS). Ozone is an air pollutant that may play a role in multiple sclerosis (MS) pathoetiology. CD86 is the only non-HLA gene associated with POMS for which expression on antigen-presenting cells (APCs) is changed in response to ozone exposure. OBJECTIVES: To examine the association between county-level ozone and POMS, and the interactions between ozone pollution, CD86, and HLA-DRB1*15, the strongest genetic variant associated with POMS. METHODS: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. County-level-modeled ozone data were acquired from the CDC's Environmental Tracking Network. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS was assessed by logistic regression. Interactions between tertiles of ozone level and the GG genotype of the rs928264 (G/A) single nucleotide polymorphism (SNP) within CD86, and the presence of DRB1*15:01 (DRB1*15) on odds of POMS were evaluated. Models were adjusted for age, sex, genetic ancestry, and mother's education. Additive interaction was estimated using relative excess risk due to interaction (RERI) and attributable proportions (APs) of disease were calculated. RESULTS: A total of 334 POMS cases and 565 controls contributed to the analyses. County-level ozone was associated with increased odds of POMS (odds ratio 2.47, 95% confidence interval (CI): 1.69-3.59 and 1.95, 95% CI: 1.32-2.88 for the upper two tertiles, respectively, compared with the lowest tertile). There was a significant additive interaction between high ozone tertiles and presence of DRB1*15, with a RERI of 2.21 (95% CI: 0.83-3.59) and an AP of 0.56 (95% CI: 0.33-0.79). Additive interaction between high ozone tertiles and the CD86 GG genotype was present, with a RERI of 1.60 (95% CI: 0.14-3.06) and an AP of 0.37 (95% CI: 0.001-0.75) compared to the lowest ozone tertile. AP results indicated that approximately half of the POMS risk in subjects can be attributed to the possible interaction between higher county-level ozone carrying either DRB1*15 or the CD86 GG genotype. CONCLUSIONS: In addition to the association between high county-level ozone and POMS, we report evidence for additive interactions between higher county-level ozone and DRB1*15 and the CD86 GG genotype. Identifying gene-environment interactions may provide mechanistic insight of biological processes at play in MS susceptibility. Our work suggests a possible role of APCs for county-level ozone-induced POMS risk.