Rebecca Straus Farber’s research while affiliated with National Multiple Sclerosis Society and other places

Background People with MS (PwMS) and related conditions treated with anti-CD20 and S1P modulating therapies exhibit attenuated immune responses to SARS-CoV-2 vaccines. It remains unclear whether humoral/T-cell responses are valid surrogates for postvaccine immunity. Objective To characterize COVID-19 vaccine-breakthrough infections in this population. Methods We conducted a prospective multicenter cohort study of PwMS and related CNS autoimmune conditions with confirmed breakthrough infections. Postvaccination antibody response, disease-modifying therapies (DMTs) at the time of vaccination, and DMT at the time of infection were assessed. Results Two hundred nine patients had 211 breakthrough infections. Use of anti-CD20 agents at time of infection was associated with increased infection severity (p = 0.0474, odds ratio (OR) = 5.923) for infections during the Omicron surge and demonstrated a trend among the total cohort (p = 0.0533). However, neither use of anti-CD20 agents at the time of vaccination nor postvaccination antibody response was associated with hospitalization risk. Anti-CD20 therapies were relatively overrepresented compared to a similar prevaccination-era COVID-19 cohort. Conclusion Use of anti-CD20 therapies during vaccine breakthrough COVID-19 infection is associated with higher severity. However, the attenuated postvaccination humoral response associated with anti-CD20 therapy use during vaccination may not drive increased infection severity. Further studies are necessary to determine if this attenuated vaccine response may be associated with an increased likelihood of breakthrough infection.

IntroductionDimethyl fumarate (DMF) showed favorable benefit-risk in patients with relapsing-remitting multiple sclerosis (MS) in phase 3 DEFINE and CONFIRM trials and in the ENDORSE extension study. Disease activity can differ in younger patients with MS compared with the overall population.Methods Randomized patients received DMF 240 mg twice daily or placebo (PBO; years 0–2 DEFINE/CONFIRM), then DMF (years 3–10; continuous DMF/DMF or PBO/DMF; ENDORSE); maximum follow-up (combined studies) was 13 years. This integrated post hoc analysis evaluated safety and efficacy of DMF in a subgroup of young adults aged 18–29 years.ResultsOf 1736 patients enrolled in ENDORSE, 125 were young adults, 86 treated continuously with DMF (DMF/DMF) and 39 received delayed DMF (PBO/DMF) in DEFINE/CONFIRM. Most (n = 116 [93%]) young adults completed DMF treatment in DEFINE/CONFIRM. Median (range) follow-up time in ENDORSE was 6.5 (2.0–10.0) years. Young adults entering ENDORSE who had been treated with DMF in DEFINE/CONFIRM had a model-based Annualized Relapse Rate (ARR; 95% CI) of 0.24 (0.16–0.35) vs. 0.56 (0.35–0.88) in PBO patients. ARR remained low in ENDORSE: 0.07 (0.01–0.47) at years 9–10 (DMF/DMF group). At year 10 of ENDORSE, EDSS scores were low in young adults: DMF/DMF, 1.9 (1.4); PBO/DMF, 2.4 (1.6). At ~ 7 years, the proportion of young adults with no confirmed disability progresion was 81% for DMF/DMF and 72% for PBO/DMF. Patient-reported outcomes (PROs) (SF-36 and EQ-5D) generally remained stable during ENDORSE. The most common adverse events (AEs) in young adults during ENDORSE were MS relapse (n = 53 [42%]). Most AEs were mild (n = 20 [23.3%], n = 7 [17.9%]) to moderate (n = 45 [52.3%], n = 23 [59.0%]) in the DMF/DMF and PBO/DMF groups, respectively. The most common serious AE (SAE) was MS relapse (n = 19 [15%]).Conclusion The data support a favorable benefit-risk profile of DMF in young adults, as evidenced by well-characterized safety, sustained efficacy, and stable PROs.Clinical Trial InformationClinical trials.gov, DEFINE (NCT00420212), CONFIRM (NCT00451451), and ENDORSE (NCT00835770).

A 53-year-old woman presented with chronic, episodic headache. The patient's headache was first noted several years prior to presentation and would occur for weeks to months, then remit for several weeks to months. More recently, the severity of the headache worsened which prompted a referral to neurology. The patient's past medical history included bilateral knee arthralgia and swelling about 6 years prior to presentation, which since resolved. While the symptoms raised the possibility of Lyme disease or rheumatoid arthritis (RA), neither diagnosis was confirmed. Given the patient's intractable headache, magnetic resonance imaging (MRI) was performed which revealed a non-enhancing left frontal white matter lesion (Figure 1A). On evaluation by neurosurgery, observation was initially recommended with the possibility of open biopsy. At follow-up, despite resolution of the patient's presenting symptom of headache, the patient began to show signs of subjective neurocognitive impairments, including word-finding difficulty, poor performance playing chess, and fear of driving. Repeat imaging 3 months since presentation revealed progression of the lesion (Figure 1B) with expansion into the temporal lobe (not shown). Given the relatively rapid radiographic progression, the lesion was biopsied with concern for a neoplastic process (Box 1). Hematoxylin and eosin (H&E)-stained sections revealed gliotic brain. Mixed chronic- and focally acute-appearing inflammatory infiltrates composed primarily of histiocytes and multinucleated giant cells, with scant lymphocytes and occasional eosinophils, involved most cortical vessels (Figure 2A–C). Transmural disruption and focal necrosis were also identified (Figure 2A), as were scattered well-formed granulomas. Cortical and leptomeningeal vessels appeared thickened and occasionally produced a double-barreled appearance. Focally exuberant perivascular hemosiderin deposits were identified. Within the vessel walls, deposition of amorphous, congophilic material was identified that appeared green-red birefringent under polarized light (Figure 2D,E). Immunohistochemistry with beta-amyloid revealed intense circumferential staining in the leptomeningeal and cortical blood vessels (Figure 2F). Final diagnosis was Amyloid beta-related angiitis (ABRA).

Objective Anxiety is common among persons with MS (PwMS), but widely accepted treatments are lacking. Group-based interventions delivered via telehealth are an accessible treatment option requiring clinical trial evidence to support feasibility and initial efficacy. We conducted a pilot feasibility trial of an online support group intervention to reduce anxiety in PwMS. Methods A non-randomized, parallel arm clinical trial was conducted. A total of 31 PwMS were enrolled: 20 completed a 12-week telehealth-delivered support group intervention and 11 were assigned to a survey-only control group. Primary feasibility outcomes were adherence and completion rates. Primary efficacy outcome was anxiety, secondary outcomes were depression, loneliness, distress, self-efficacy, stress, and quality of life. Results Twenty-six participants completed the study. Intervention group adherence (75%) and completion (85%) rates were acceptable. Results indicated a medium size between-group effect, suggesting a greater reduction in anxiety in the intervention group compared to the control group [U = 39.50, p = 0.045, r = 0.39]. No group differences in other outcomes were observed. Conclusion A telehealth-delivered support group intervention appears feasible for further study and shows initial efficacy for the reduction of anxiety in PwMS.

It has been hypothesized that multiple sclerosis (MS) has hormonal influences, and testosterone may have anti-inflammatory functions in this context. Given prior reports of lower testosterone levels in men with MS in archival serum samples, we evaluated the prevalence of hypogonadism in the clinical setting and its association with disability in men with MS. Subjects were screened for symptoms of hypogonadism using a clinical instrument, and those with positive screens had total and free morning testosterone levels checked. Of the 64 subjects who were screened, 50 (78%) had positive results, and 46 (92%) had morning testosterone levels checked. Among the latter, 5 were found to have testosterone levels below lower limit of normal. Other than the expected inverse relation with BMI, testosterone did not correlate with demographic or disease related factors. Baseline testosterone did not predict risk of EDSS or T25-FW progression or future MRI activity.

Background: Patients with autoimmune disease and on immunotherapy were largely excluded from seminal vaccine trials. This has led to significant vaccine hesitancy in patients with neuroinflammatory diseases (NID); including, but not limited to: multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), neurosarcoidosis and myelin oligodendrocyte antibody-mediated disease (MOG-AD). Data is urgently needed to help guide clinical care in the NID population. Methods: This was a cross-sectional observational study evaluating adults with a neurologist-confirmed diagnosis of a neuroinflammatory disease (NID) and a neurologically asymptomatic control population. Participants were recruited from multiple academic centers in the MS Resilience to COVID-19 Collaborative study. We analyzed participant responses from a vaccine-specific questionnaire collected between February and May 2021. Results: 1164 participants with NID and 595 controls completed the vaccine survey. Hesitancy rates were similar between NID and control groups (n=134, 32.7% NID vs. n=56, 30.6% control; p=0.82). The most common reasons for hesitancy in NID participants were lack of testing in the autoimmune population and fear of demyelinating/neurologic event. Unvaccinated patients who had discussed vaccination with their doctor were less likely to be hesitant (n=184, 73.6% vs. n=83, 59.7%; p=0.007). 634 NID patients and 332 controls had received at least one dose of a vaccine against SARS-CoV-2 at the time of survey completion. After adjusting for age, BMI, and comorbidities, there was no difference in self-reported side effects (SE) between groups with the first dose (n=256, 42.2% NID vs. 141, 45.3% control; p=0.20) or second dose (n=246, 67.0% NID vs. n=114, 64.8% control, p=0.85) of the mRNA vaccines nor with the viral-vector vaccines (n=6, 46% NID vs. n= 8, 66% control; p= 0.39). All reported SEs fell into the expected SE profile. There was no difference in report of new/recurrent neurologic symptoms (n = 110, 16.2% vaccinated vs. 71, 18.2% unvaccinated; p =0.44) nor radiologic disease activity (n=40, 5.9% vaccinated vs. n=30, 7.6% unvaccinated) between vaccinated and unvaccinated NID participants. Conclusions: We found no difference in patient-reported vaccine side effects and no evidence of NID worsening after vaccination. Large-scale real-world evidence is needed for further validation.

Background While many patients with myelin oligodendrocyte glycoprotein antibody-mediated disease (MOG-AD) will have a monophasic course, 30-80% of patients will relapse after the initial attack. It is not known which factors predict relapse. Here we describe our clinical experience with MOG-AD and evaluate for factors that correlate with relapsing disease. Methods This was a retrospective, multi-institutional study of 54 patients with MOG-AD, including 17 children and 37 adults. Mann-Whitney U and Fischer's Exact tests were used for comparisons and logistic regression for correlations. Results Incident attack phenotype included acute disseminated encephalomyelitis (15%), unilateral optic neuritis (ON; 39%), bilateral ON (24%), transverse myelitis (TM; 11%) and ON with TM (11%). Pediatric patients were more likely than adults to present with ADEM (p= .009) and less likely to present with unilateral ON (p =.04). 31 patients (57%) had a relapsing disease course, with time to first relapse of 8.2 months and median annualized relapse rate of 0.97 months. In 40% of patients (n=22) the first relapse occurred following the withdrawal of treatment for the incident attack. 5 patients converted to seronegative at follow up, 2 of whom later relapsed. Logistic regression revealed no significant relationship between age, gender, race, presentation phenotype, antibody titer, or cerebrospinal fluid results with risk of relapse. For patients who started disease modifying therapy (DMT) prior to the first relapse (n=11), 64% remained monophasic. 50% (n=15) of patients on DMT continued to have disease activity, requiring treatment adjustment. Conclusions It is difficult to predict which patients with MOG-AD will relapse. Research is needed to determine the optimal timing and choice of treatment.