Worsening of lymphopenia in patients with multiple sclerosis when switched from dimethyl fumarate to diroximel fumarate.

BACKGROUND: Diroximel fumarate (DRF) and dimethyl fumarate (DMF) are similar disease-modifying therapies (DMTs) that reduce disease activity in patients with relapsing-remitting multiple sclerosis (MS). We expect that patients on DRF would experience a similar incidence and severity of lymphopenia, given that it is a well-documented side effect of DMF treatment. METHODS: We utilized linear mixed-effects models to test for differences in white blood cell count (WBC), absolute lymphocyte count (ALC), absolute CD3+ count, absolute CD4+ count, and absolute CD8+ count over time in clinically stable patients with MS on DMF who switched to DRF. RESULTS: Twenty-two patients with MS who were clinically stable on DMF switched to DRF. Linear mixed-effects models showed a decrease in ALC when switching medications (ß = -225.70, p < 0.040). In addition, the models showed a decrease in absolute CD8+ counts after switches from DMF to DRF (ß = -85.59, p = 0.034). CONCLUSION: Patients with MS who are stable on DMF and switch to DRF may experience worsening of lymphopenia and lower absolute CD8+ counts, which may increase their risk of opportunistic infections. These findings indicate that close lymphocyte subset monitoring is clinically important when switching patients with MS from DMF to DRF.

Altered lymphocyte profiles and herpes zoster infections in patients with multiple sclerosis on natalizumab.

Cases of herpes zoster (HZ) in patients with MS on natalizumab (NTZ) have been documented. In this study, we assessed lymphocyte subsets in NTZ-treated patients with HZ compared to matched controls without HZ. Twenty unvaccinated patients developed HZ while on NTZ for an incidence rate of 12.3 per 1000 patient-years. These patients had lower CD8+% and higher CD4+:CD8+ ratios (p ⩽ 0.01) than non-HZ matched controls. Two patients with relapsing-remitting MS developed HZ twice while on NTZ. These findings underscore the importance of pre-NTZ HZ vaccination due to potential HZ risk.

Clinical course of multiple sclerosis with comorbid endometriosis: A matched cohort study.

BACKGROUND: Endometriosis (EMS) is pain syndrome in which endometrial tissue grows outside the uterus. EMS is associated with an increased risk of multiple sclerosis (MS), a demyelinating disease of the central nervous system. OBJECTIVE: To characterize clinical phenotypes of a cohort of patients with both EMS and MS compared to a cohort of matched controls with only MS. METHODS: We retrospectively identified patients with EMS and MS at Beth Israel Deaconess Medical Center (BIDMC). We collected data on EMS treatments and analyzed differences in histories of gynecological cancer, smoking, fatigue, anxiety, depression, headache, and neuropathic pain compared to matched controls. We used Wilcoxon signed rank tests for paired samples to compare Expanded Disability Status Scores (EDSS) and timed 25-foot walk values (T25FW). RESULTS: Using a case-control methodology, we found significantly increased EDSS (p < 0.001) and T25FW (p = 0.01) in the EMS-MS group compared to the MS group. More patients in the EMS-MS group had histories of smoking, anxiety, depression, and headaches, while more patients in the MS group had histories of fatigue and neuropathic pain. CONCLUSION: When controlling for age, race, and MS therapy, those with EMS-MS experience more MS disability than controls, suggesting this population requires more monitoring and efficacious treatment.

Bariatric surgery outcomes in multiple sclerosis: Interplay with vitamin D and chronic pain syndromes.

BACKGROUND: Obesity and lower vitamin D levels are associated with adverse outcomes in multiple sclerosis (MS). Bariatric surgery is a safe intervention in patients with MS, although it lowers vitamin D levels in the general population. OBJECTIVE: To investigate the effects of bariatric surgery on vitamin D levels and interrogate risk factors for unsuccessful post-operative weight loss in patients with MS. METHODS: We retrospectively identified patients with MS who underwent bariatric surgery from 2001 to 2023. Wilcoxon signed rank tests for paired samples were used to compare pre- and post-operative body mass index (BMI), expanded disability status scale (EDSS), timed 25-foot walk (T25FW), and median vitamin D values. RESULTS: Following bariatric surgery, patients with MS had a decrease in BMI (mean percent total weight loss of 18.4 %, range 0-38 %, p < 0.001) and an increase in vitamin D values (mean increase of 23 ng/mL, range -4-32 ng/mL, p < 0.001), while no change in EDSS or T25FW was seen. Four out of 20 patients did not lose more than 5 % of their pre-operative BMI, all of whom had chronic pain syndromes and were on gabapentin. CONCLUSION: Healthy vitamin D levels are attainable following bariatric surgery in patients with MS.

High CD4+:CD8+ ratios with herpes zoster infections in patients with multiple sclerosis on dimethyl fumarate.

BACKGROUND: Dimethyl fumarate (DMF) depletes CD8+ and CD4+ T cells, and cases of herpes zoster (HZ) in patients with multiple sclerosis (MS) on DMF have been documented. OBJECTIVES: To evaluate lymphocyte subsets in patients with MS who developed HZ on DMF (Tecfidera) compared to matched controls who did not develop HZ. METHODS: We used linear mixed-effects models to test for differences in white blood cell count, lymphocyte percentage, absolute lymphocyte count, CD3+ percentage, absolute CD3+ count, CD4+ percentage, absolute CD4+ count, CD8+ percentage, absolute CD8+ count, and CD4+:CD8+ ratio over time in HZ and non-HZ groups. RESULTS: Eighteen patients developed HZ while on DMF. The linear mixed-effects model for CD4+:CD8+ ratio showed a significant difference between the HZ and non-HZ groups (p = 0.033). CD4+:CD8+ ratio decreased over time in the HZ group and increased over time in the non-HZ group. CONCLUSION: Patients with MS who develop HZ while on DMF have high CD4+:CD8+ ratios, suggesting an imbalance of CD4+ and CD8+ cells that may put a patient at risk for developing HZ while on DMF. This result emphasizes the need for lymphocyte subset monitoring (including CD4+:CD8+ ratios) on DMF, as well as vaccination prior to DMF initiation.

Blunted Post-COVID-19 Humoral Immunity in Patients With CNS Demyelinating Disorders on Anti-CD20 Treatments.

With unclear characteristics of post-infection and post-vaccination immunity, the multiple sclerosis community lacks evidence to guide patients on their continued coronavirus disease 2019 (COVID-19) infection risk. As disease modifying treatments all modulate the immune system, we expect their use to alter acquired immunity to COVID-19, but the specific impact of individual treatments is unclear. To address this, we analyzed the patient and COVID-19 specific characteristics associated with post-infection humoral immunity in 58 patients with central nervous system (CNS) demyelinating disorders in the Boston metropolitan area. Univariate analysis of variance was performed using Mann Whitney U test for continuous variables, and Chi Square or Fisher Exact test for nominal variables. Univariate and stepwise multivariate nominal logistic regression identified clinical characteristics associated with COVID-19 specific nucleocapsid IgG antibody formation post-infection. Our cohort demonstrated a 42% post-infection seropositive rate with a significantly higher rate observed with shorter duration between infection and antibody collection and use of natalizumab over no/other treatment. Use of anti-CD20 treatments compared to no/other treatment was associated with a significantly lower rate of seropositivity. However, only shorter duration between infection and antibody collection as well as use of no/other treatment compared to anti-CD20 treatment were found to be independently associated with increased likelihood of post-infection seropositivity. Additionally, we demonstrate durability of antibody response up to 9 months in a small subset of patients. Thus, our data supports that patients with CNS demyelinating disorders regardless of DMT are able to form a measurable antibody response after COVID-19 infection, and that patients on anti-CD20 treatments form less robust immunity after COVID-19 infection.

A New England COVID-19 Registry of Patients With CNS Demyelinating Disease: A Pilot Analysis.

BACKGROUND AND OBJECTIVES: We sought to define the risk of severe coronavirus disease 2019 (COVID-19) infection requiring hospitalization in patients with CNS demyelinating diseases such as MS and the factors that increase the risk for severe infection to guide decisions regarding patient care during the COVID-19 pandemic. METHODS: A pilot cohort of 91 patients with confirmed or suspected COVID-19 infection from the Northeastern United States was analyzed to characterize patient risk factors and factors associated with an increased severity of COVID-19 infection. Univariate analysis of variance was performed using the Mann-Whitney U test or analysis of variance for continuous variables and the χ2 or Fisher exact test for nominal variables. Univariate and stepwise multivariate logistic regression identified clinical characteristics or symptoms associated with hospitalization. RESULTS: Our cohort demonstrated a 27.5% hospitalization rate and a 4.4% case fatality rate. Performance on Timed 25-Foot Walk before COVID-19 infection, age, number of comorbidities, and presenting symptoms of nausea/vomiting and neurologic symptoms (e.g., paresthesia or weakness) were independent risk factors for hospitalization, whereas headache predicted a milder course without hospitalization. An absolute lymphocyte count was lower in hospitalized patients during COVID-19 infection. Use of disease-modifying therapy did not increase the risk of hospitalization but was associated with an increased need for respiratory support. DISCUSSION: The case fatality and hospitalization rates in our cohort were similar to those found in MS and general population COVID-19 cohorts within the region. Hospitalization was associated with increased disability, age, and comorbidities but not disease-modifying therapy use.

Prevalence of Latent Tuberculosis in the Multiple Sclerosis Clinic and Effect of Multiple Sclerosis Treatment on Tuberculosis Testing.

BACKGROUND: Patients with a compromised immune system are at risk for converting from latent tuberculosis infection (LTBI) to active tuberculosis (TB) infection. Multiple sclerosis (MS) therapies may put individuals with LTBI at higher risk of TB. METHODS: Patients at the Beth Israel Deaconess Medical Center MS Clinic were screened for TB as part of routine testing with the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay (Cellestis Ltd) from 2013 to 2017. Patients were tested either before or during immunomodulatory therapy. RESULTS: Four of 222 patients (1.8%; 95% CI, 0.1%-3.6%) had positive QFT-GIT results; three patients had risk factors for TB, having emigrated from TB-endemic countries or worked in the health care industry. Twenty-eight of 222 patients (12.6%) had an indeterminate assay result, and 75.0% of these occurred in patients taking dimethyl fumarate. Fingolimod, natalizumab, or anti-CD20 treatments showed 0% to 7.7% indeterminate results. CONCLUSIONS: The prevalence of LTBI was 1.8% in the Beth Israel Deaconess Medical Center MS Clinic. Not all LTBI cases were associated with known risk factors for TB. Screening for LTBI before starting immunosuppressive agents for MS could help prevent activation of TB. Dimethyl fumarate use is associated with indeterminate QFT-GIT results, possibly due to functional effects on lymphocytes and levels of cytokines, such as interferon gamma. In contrast, fingolimod use was rarely associated with indeterminate QFT-GIT results despite a high rate of lymphopenia in virtually all patients.

Brainstem lesions are associated with sleep apnea in multiple sclerosis.

BACKGROUND: Studies linking MRI findings in MS patients with obstructive sleep apnea severity are limited. OBJECTIVE: We conducted a retrospective study to assess MRI abnormalities associated with obstructive sleep apnea (OSA) in patients with multiple sclerosis (MS). METHODS: We performed retrospective chart review of 65 patients with multiple sclerosis who had undergone polysomnography (PSG) for fatigue as well as brain MRI. We measured the number of lesions in the brainstem and calculated the standardized third ventricular width (sTVW) as a measure of brain atrophy, and subsequently performed correlation analyses of the apnea-hypopnea index (AHI) with brainstem lesion location, sTVW, and Expanded Disability Status Scale (EDSS). RESULTS: MS Patients with OSA were significantly older and had a higher body mass index (BMI) and higher AHI measures than patients without OSA. After adjustment for covariates, significant associations were found between AHI and lesion burden in the midbrain (p < 0.01) and pons (p = 0.05), but not medulla. CONCLUSIONS: Midbrain and pontine lesions burden correlated with AHI, suggesting MS lesion location could contribute to development of OSA.

Anti-JC virus antibody index changes in rituximab-treated multiple sclerosis patients.

Rituximab, a monoclonal antibody to CD20, is an effective treatment for relapsing remitting multiple sclerosis (MS) reducing relapse rate by at least 50% over time. Although the mechanism for this clinical benefit is unclear, rituximab depletes circulating B cells, which can perform antigen presentation and stimulation of T cells. Another anti-CD20 drug, ocrelizumab, has recently been FDA approved to treat both relapsing remitting and progressive forms of MS. While long-term effects of ocrelizumab use are essentially unknown, long-term use of rituximab has been associated with the development of progressive multifocal leukoencephalopathy (PML) at an incidence of approximately 1/25,000 in non-MS conditions. Serostatus for JC virus (JCV), the causative agent for PML, is an important risk stratification tool for natalizumab, but its utility in other MS treatments is uncertain. We found that rituximab use was associated with a reduction in JCV antibody index values in MS patients. Reductions in immunoglobulins, IgM in particular, are seen in concert with JCV antibody reductions. Physicians should exercise caution when using JCV antibody indices to assess any risk of PML for patients on rituximab.