Transitioning From S1P Receptor Modulators to B Cell-Depleting Therapies in Multiple Sclerosis: Clinical, Radiographic, and Laboratory Data.

BACKGROUND AND OBJECTIVES: Patients with multiple sclerosis (MS) transition from oral sphingosine-1-receptor (S1P) modulators to anti-CD20 therapies for several circumstances. Optimal timing of this transition is uncertain, given competing concerns of rebound disease activity and ensuring immune reconstitution. The objective of this study was to evaluate the relationship between inflammatory activity and the transition period from fingolimod to anti-CD20 therapies in a real-world MS cohort. METHODS: Medical records were reviewed for all patients at our center transitioning from fingolimod to rituximab or ocrelizumab between 2010 and October 2020. Time periods reviewed were the following: before fingolimod discontinuation, interval between fingolimod and anti-CD20 treatments, and after the first anti-CD20 infusion. The primary outcome was clinical relapses; MRI activity, time to absolute lymphocyte count (ALC) recovery, and infections were secondary. Clinical and demographic factors significant in univariable analyses were included in multivariable analyses. RESULTS: Transition data were available for 108 patients (68.5% women, 68.5% relapsing-remitting MS, mean age 44.6 years). The median (interquartile range) interval between fingolimod and anti-CD20 therapy was 28 (1-115.2) days. Six of 51 patients (11.8%) with intervals >1 month and 0/57 patients with shorter intervals experienced a relapse (MRI confirmed) within 6 months of fingolimod discontinuation. In the year following anti-CD20 initiation, 4/108 patients (3.7%) experienced a relapse (median 214.5 days after infusion). An additional 7% of those undergoing contrast-enhanced MRIs developed Gd+ lesions. ALC normalized following treatment switch in 89/92; the interval between treatments was unrelated to ALC recovery or infection. DISCUSSION: Delaying anti-CD20 start to monitor ALC after S1P modulator discontinuation may not be necessary and could increase rebound risk. ALC monitoring could instead occur after a rapid switch to anti-CD20 treatment.

Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis.

BACKGROUND AND OBJECTIVES: To study human leukocyte antigen (HLA) allele associations in anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis. METHODS: A multiethnic cohort of 269 patients with anti-LGI1 encephalitis and 1,359 controls was included. Four-digit HLA sequencing and genome wide association single-nucleotide polymorphism typing imputation (0.99 concordance) were used for HLA typing. Significance of primary and secondary associations was tested using χ2, Fisher exact tests, or logistic regression with the control of population stratification covariates when applicable. RESULTS: DRB1*07:01 and DQA1*02:01, 2 alleles in strong linkage disequilibrium, were associated with the disease (90% vs 24%, OR = 27.8, p < 10e-50) across ethnicity independent of variation at DRB3 and DQB1, 2 flanking HLA loci. DRB1*07:01 homozygosity was associated with a doubling of risk (OR = 2.1, p = 0.010), suggesting causality. DRB1*07:01 negative subjects were younger (p = 0.003) and more frequently female (p = 0.015). Three patients with malignant thymomas did not carry DRB1*07:01, whereas patients with other tumors had high DRB1*07:01 frequency, suggesting that the presence of tumors other than thymomas may be coincidental and not causal. In both DRB1*07:01 heterozygous individuals and DRB1*07:01 negative subjects, DRB1*04:02 was associated with anti-LGI1 encephalitis, indicating an independent effect of this allele (OR = 6.85, p = 4.57 × 10-6 and OR = 8.93, p = 2.50 × 10-3, respectively). DRB1*04:02 was also independently associated with younger age at onset (ß = -6.68, p = 9.78 × 10-3). Major histocompatibility complex peptide-binding predictions using LGI1-derived peptides revealed divergent binding propensities for DRB1*04:02 and DRB1*07:01 alleles, suggesting independent pathogenic mechanisms. DISCUSSION: In addition to the established primary DRB1*07:01 association in anti-LGI1 encephalitis, we observe a secondary effect of DRB1*04:02 with lower age at onset. Our study provides evidence for secondary effects within HLA locus that correlate with clinical phenotypes in anti-LGI1 encephalitis.

The state of clinical research in neurology.

OBJECTIVE: To study and provide an update on the state of clinical research in neurology in the United States. METHODS: US American Academy of Neurology members and chairs of departments of neurology were surveyed regarding clinical research in 2016. NIH data on the neuroscience pipeline and extramural grant funding were also collected. RESULTS: The response rate was 32% (n = 254) for nonchair researchers and 58% (n = 67) for department chairs. Researcher respondents were on average 50 years old, 66% were men, and 81% were actively conducting clinical research, with phase II/III clinical trials and outcome measure studies being the most common type of research conducted. Time to conduct research, recruitment, and administrative burden were the major barriers reported. According to department chairs, funding and training opportunities in patient-oriented research have increased over the last 10 years. Overall, applicants to neuroscience-specific NIH institutes for extramural funding have decreased over the same time period. CONCLUSIONS: The state of clinical research in neurology has remained relatively stable over the last 10 years, but neurologists still have barriers in conducting clinical research. There has been an interval decrease in neuroscience applicants for NIH funding, which raises concerns about the pipeline and future of clinical research in neurology. These results will serve as a reference for the development of solutions to these issues.