Key characteristics of anti-CD20 monoclonal antibodies and clinical implications for multiple sclerosis treatment.

The recent success of anti-CD20 monoclonal antibody therapies in the treatment of multiple sclerosis (MS) has highlighted the role of B cells in the pathogenesis of MS. In people with MS, the inflammatory characteristics of B-cell activity are elevated, leading to increased pro-inflammatory cytokine release, diminished anti-inflammatory cytokine production and an accumulation of pathogenic B cells in the cerebrospinal fluid. Rituximab, ocrelizumab, ofatumumab, ublituximab and BCD-132 are anti-CD20 therapies that are either undergoing clinical development, or have been approved, for the treatment of MS. Despite CD20 being a common target for these therapies, differences have been reported in their mechanistic, pharmacological and clinical characteristics, which may have substantial clinical implications. This narrative review explores key characteristics of these therapies. By using clinical trial data and real-world evidence, we discuss their mechanisms of action, routes of administration, efficacy (in relation to B-cell kinetics), safety, tolerability and convenience of use. Clinicians, alongside patients and their families, should consider the aspects discussed in this review as part of shared decision-making discussions to improve outcomes and health-related quality of life for people living with MS.

Identification and management of subclinical disease activity in early multiple sclerosis: a review.

IMPORTANCE: Early treatment initiation in multiple sclerosis (MS) is crucial in preventing irreversible neurological damage and disability progression. The current assessment of disease activity relies on relapse rates and magnetic resonance imaging (MRI) lesion activity, but inclusion of other early, often "hidden," indicators of disease activity may describe a more comprehensive picture of MS. OBSERVATIONS: Early indicators of MS disease activity other than relapses and MRI activity, such as cognitive impairment, brain atrophy, and fatigue, are not typically captured by routine disease monitoring. Furthermore, silent progression (neurological decline not clearly captured by standard methods) may occur undetected by relapse and MRI lesion activity monitoring. Consequently, patients considered to have no disease activity actually may have worsening disease, suggesting a need to revise MS management strategies with respect to timely initiation and escalation of disease-modifying therapy (DMT). Traditionally, first-line MS treatment starts with low- or moderate-efficacy therapies, before escalating to high-efficacy therapies (HETs) after evidence of breakthrough disease activity. However, multiple observational studies have shown that early initiation of HETs can prevent or reduce disability progression. Ongoing randomized clinical trials are comparing escalation and early HET approaches. CONCLUSIONS AND RELEVANCE: There is an urgent need to reassess how MS disease activity and worsening are measured. A greater awareness of "hidden" indicators, potentially combined with biomarkers to reveal silent disease activity and neurodegeneration underlying MS, would provide a more complete picture of MS and allow for timely therapeutic intervention with HET or switching DMTs to address suboptimal treatment responses.

Secondary hypogammaglobulinemia in patients with multiple sclerosis on anti-CD20 therapy: Pathogenesis, risk of infection, and disease management.

Hypogammaglobulinemia is characterized by reduced serum immunoglobulin levels. Secondary hypogammaglobulinemia is of considerable interest to the practicing physician because it is a potential complication of some medications and may predispose patients to serious infections. Patients with multiple sclerosis (MS) treated with B-cell-depleting anti-CD20 therapies are particularly at risk of developing hypogammaglobulinemia. Among these patients, hypogammaglobulinemia has been associated with an increased risk of infections. The mechanism by which hypogammaglobulinemia arises with anti-CD20 therapies (ocrelizumab, ofatumumab, ublituximab, rituximab) remains unclear and does not appear to be simply due to the reduction in circulating B-cell levels. Further, despite the association between anti-CD20 therapies, hypogammaglobulinemia, and infections, there is currently no generally accepted monitoring and treatment approach among clinicians treating patients with MS. Here, we review the literature and discuss possible mechanisms of secondary hypogammaglobulinemia in patients with MS, hypogammaglobulinemia results in MS anti-CD20 therapy clinical trials, the risk of infection for patients with hypogammaglobulinemia, and possible strategies for disease management. We also include a suggested best-practice approach to specifically address secondary hypogammaglobulinemia in patients with MS treated with anti-CD20 therapies.

A plain language summary on assessing the long-term effectiveness of cladribine tablets in people living with relapsing multiple sclerosis: The CLASSIC-MS study.

WHAT IS THIS SUMMARY ABOUT?: Previous studies have shown that people living with multiple sclerosis (MS) treated with cladribine tablets have fewer relapses (where new symptoms occur or existing symptoms get worse for 24 hours or more) and delayed disability progression (slowing down of the disease getting worse). The CLASSIC-MS study looked at the long-term effectiveness of treatment with cladribine tablets in people living with MS who had taken part in the original CLARITY and CLARITY Extension clinical studies. WHAT WERE THE RESULTS?: Results showed that people treated with cladribine tablets maintained their mobility (the ability to move freely) for longer and experienced other positive effects long after their treatment ended, including being less likely to need further treatment for their MS. WHAT DO THE RESULTS MEAN?: The results obtained from CLASSIC-MS show that the benefits of taking cladribine tablets carry on even when patients stop taking the treatment.

Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study.

BACKGROUND: CLASSIC-MS evaluated the long-term efficacy of cladribine tablets in patients with relapsing multiple sclerosis. OBJECTIVE: Report long-term mobility and disability beyond treatment courses received in CLARITY/CLARITY Extension. METHODS: This analysis represents CLASSIC-MS patients who participated in CLARITY with/without participation in CLARITY Extension, and received ⩾1 course of cladribine tablets or placebo (N = 435). Primary objective includes evaluation of long-term mobility (no wheelchair use in the 3 months prior to first visit in CLASSIC-MS and not bedridden at any time since last parent study dose (LPSD), i.e. Expanded Disability Status Scale (EDSS) score <7). Secondary objective includes long-term disability status (no use of an ambulatory device (EDSS < 6) at any time since LPSD). RESULTS: At CLASSIC-MS baseline, mean ± standard deviation EDSS score was 3.9 ± 2.1 and the median time since LPSD was 10.9 (range = 9.3-14.9) years. Cladribine tablets-exposed population: 90.6% (N = 394), including 160 patients who received a cumulative dose of 3.5 mg/kg over 2 years. Patients not using a wheelchair and not bedridden: exposed, 90.0%; unexposed, 77.8%. Patients with no use of an ambulatory device: exposed, 81.2%; unexposed, 75.6%. CONCLUSION: With a median 10.9 years' follow-up after CLARITY/CLARITY Extension, findings suggest the sustained long-term mobility and disability benefits of cladribine tablets.

Bruton's Tyrosine Kinase Inhibitors: The Next Frontier of B-Cell-Targeted Therapies for Cancer, Autoimmune Disorders, and Multiple Sclerosis.

Bruton's tyrosine kinase (BTK) is an important protein belonging to the tyrosine kinase family that plays a key role in the intracellular signaling and proliferation, migration, and survival of normal and malignant B-lymphocytes and myeloid cells. Understanding the role of BTK in the B-cell signaling pathway has led to the development of BTK inhibitors (BTKi) as effective therapies for malignancies of myeloid origin and exploration as a promising therapeutic option for other cancers. Given its central function in B-cell receptor signaling, inhibition of BTK is an attractive approach for the treatment of a wide variety of autoimmune diseases that involve aberrant B-cell function including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). Here, we review the role of BTK in different cell signaling pathways, the development of BTKi in B-cell malignancies, and their emerging role in the treatment of MS and other autoimmune disorders.

Disease stability over five years in people with multiple sclerosis treated with cladribine tablets: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article originally published in the journal Advances in Therapy. Cladribine tablets are approved for treating people with relapsing multiple sclerosis (shortened to MS). People with MS take cladribine tablets for 2 periods of 4 to 5 days per year. This analysis looks at the results from 2 studies called the CLARITY and CLARITY Extension studies. These studies looked at what effect a 2-year course of treatment with cladribine tablets had on disability over 5 years in people with MS. HOW WAS THE ANALYSIS CARRIED OUT?: In this analysis, researchers measured disability worsening at regular intervals during the 2-year treatment period in the CLARITY study and thereafter in the 2-year CLARITY Extension study. As many patients had a bridging interval between CLARITY and CLARITY extension, the researchers were able to assess disability over a 5-year timeframe. WHAT WERE THE RESULTS?: When measurements were taken at Year 5 of the study, disability remained stable in more than half of participants. Over the 5-year period, 70% of participants did not experience persistent disease worsening that lasted more than 6 months. WHAT DO THE RESULTS MEAN?: Researchers concluded that a 2-year course of cladribine tablets may provide long-term benefits on disability for up to 5 years. Clinical Trial Registration: NCT00213135 (ClinicalTrials.gov) Clinical Trial Registration: NCT00641537 (ClinicalTrials.gov).

Relapses in people with multiple sclerosis treated with cladribine tablets followed for up to 5 years: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article originally published in the Multiple Sclerosis Journal. The article presents the results from the CLARITY and CLARITY Extension studies, which looked at how well cladribine tablets work in treating people with multiple sclerosis (shortened to MS). Cladribine tablets are a medication approved for treating relapsing forms of MS. This study looked at how treatment with cladribine tablets affects the frequency and severity of relapses in people with MS. A relapse is when new symptoms develop or old symptoms return or get worse after a period of stability or improvement. WHAT HAPPENED IN THE STUDIES?: In the CLARITY study, 870 people received either cladribine tablets (3.5 mg/kg, the approved dose) or placebo (a dummy pill). After the CLARITY study ended, some participants who received cladribine tablets chose to take part in a second study called the CLARITY Extension study. Of these participants, 98 were given placebo for 2 more years following an interval period of up to 10 months between participating in each study. WHAT WERE THE RESULTS?: People with MS who were treated with cladribine tablets for 2 years in the CLARITY study had lower risks of any relapse compared with those given placebo. Participants taking placebo (after cladribine tablets) in the CLARITY Extension study experienced these same benefits, which continued for up to 3 more years after having received cladribine tablets in the CLARITY study. WHAT DO THE RESULTS MEAN?: Researchers concluded the recommended 2-year dosing of cladribine tablets may reduce the number and severity of relapses in people with MS for up to 5 years. Clinical Trial Registration: NCT00213135 (ClinicalTrials.gov) Clinical Trial Registration: NCT00641537 (ClinicalTrials.gov).

COVID-19 in the pregnant or postpartum MS patient: Symptoms and outcomes.

Women with multiple sclerosis (MS) are often of childbearing age. Thirty-six women with MS who were pregnant (n = 27) or within 6 weeks postpartum (n = 9) were reported in the North American COViMS registry and their COVID-19 outcomes were described. One pregnant and one postpartum woman were hospitalized. No deaths occurred. To compare COVID-19 clinical outcomes in pregnant and postpartum females with females who were not pregnant or postpartum, a 1:2 propensity score match was performed. While not powered to detect small differences, it was reassuring that no increased risks for those with MS who were pregnant/postpartum were revealed.

Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: The CLARITY and CLARITY Extension studies.

BACKGROUND: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study of patients with relapsing-remitting multiple sclerosis, treatment with cladribine tablets 3.5 mg/kg (CladT) significantly reduced the annualised relapse rate (ARR) versus placebo; this effect was sustained in CLARITY Extension, without further treatment. OBJECTIVE: To assess the frequency and severity of relapses in patients treated with CladT versus placebo in CLARITY over 2 years and evaluate the durability of effect in patients who received no further treatment for 2 years in CLARITY Extension. METHODS: In this post hoc analysis, ARRs were calculated for qualifying and all relapses, and qualifying and all severe relapses (i.e. requiring steroid treatment or leading to hospitalisation) in patients treated with CladT (n = 433) and placebo (n = 437) in CLARITY, and those from the CladT group who received placebo in CLARITY Extension (n = 98). RESULTS: At Month 6, Year 1 and Year 2, patients receiving CladT had a significantly lower risk of qualifying or all relapses (all p < 0.0001), and qualifying or all severe relapses (all p < 0.005), compared with placebo. This effect was sustained in CLARITY Extension without further treatment. CONCLUSION: The results show durable efficacy of cladribine tablets 3.5 mg/kg for reducing frequency and severity of relapses in patients with relapsing-remitting multiple sclerosis.CLARITY: NCT00213135; CLARITY Extension: NCT00641537.

Peripheral nervous system electrodiagnostic abnormalities in predominantly Hispanic Multiple Sclerosis patients.

BACKGROUND: Peripheral nervous system (PNS) abnormalities in Multiple Sclerosis (MS) have been reported in case reports and small case series over the past several decades. Little is known, however, about the prevalence of electrodiagnostic abnormalities in patients with MS, including not only demyelinating neuropathies such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but also axonal peripheral neuropathy and sympathetic dysfunction. METHODS: This is an observational, cross-sectional study with the objective of identifying the prevalence of the electrodiagnostic abnormalities in predominantly Hispanic MS patients in Miami, Florida. Electrodiagnostic data including nerve conduction study (NCS), electromyography (EMG) and sympathetic skin response (SSR) information was prospectively collected in 18 patients (16 females; 43.7±15.2 years) with a diagnosis of MS compared to 18 healthy (16 females; 39.9±11 years), age- and height-matched controls. The study was offered to all-comers in the MS Clinic over a period of 3 months, regardless of clinical suspicion for an underlying neuropathic process, in an effort to estimate the prevalence of abnormalities. Demographic data including age, sex, race/ethnicity was evaluated in addition to MS-specific characteristics including MS subtype, duration of disease, duration of therapy, clinical symptoms and laboratory data. RESULTS: There were no significant differences in baseline characteristics of patients and controls for age (p=0.4) and height (164.0±6.4 vs 162.3±4.6 centimeters; p=0.3). The mean disease duration was 106±27 months (median 107 months; range 5-336 months). The mean Expanded Disability Status Scale (EDSS) was 2.4±1.87 (median: 2.5; range 1.0-6.5). The ethnicity of patients (15 Hispanic, 3 non-Hispanic) and controls (13 Hispanic, 5 non-Hispanic; p=0.56) was similar. The frequency of electrophysiological axonal polyneuropathy (PN) was 77.8% (14/18 patients), and 85.6% of these patients had clinical sensory symptoms. Interestingly, 1 patient had previously unrecognized CIDP. All 18 patients displayed prolonged SSR latencies consistent with autonomic dysfunction. Thirteen patients (72.2%) reported autonomic symptoms such as bladder abnormalities and blood pressure fluctuations. CONCLUSION: The prevalence of electrodiagnostic abnormalities, especially axonal polyneuropathy, in the MS population may be higher than traditionally considered. The relationship between axonal polyneuropathy and central axonopathy in the context of neurodegeneration in MS should be further explored. Analytic studies may identify common symptomatic and pathophysiologic etiologies to further understanding and potentially guide treatment of MS subtypes with PNS involvement.

Long-Term Disease Stability Assessed by the Expanded Disability Status Scale in Patients Treated with Cladribine Tablets 3.5 mg/kg for Relapsing Multiple Sclerosis: An Exploratory Post Hoc Analysis of the CLARITY and CLARITY Extension Studies.

INTRODUCTION: In the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study, cladribine tablets significantly reduced relapse rates and improved findings on magnetic resonance imaging versus placebo in patients with relapsing multiple sclerosis. In the CLARITY Extension study, treatment with cladribine tablets for 2 years followed by placebo for 2 years produced similar clinical benefits to 4 years of cladribine tablets. The objective of this exploratory post hoc analysis was to evaluate long-term disease stability (assessed by the Expanded Disability Status Scale [EDSS] score) after treatment with cladribine tablets. METHODS: Patients enrolled into CLARITY Extension who were previously randomized to cladribine tablets 3.5 mg/kg in the CLARITY study were included in this post hoc analysis. Two treatment groups were investigated-patients randomized to cladribine tablets 3.5 mg/kg in CLARITY and thereafter randomized to placebo in CLARITY Extension (the CP3.5 group) or to cladribine tablets 3.5 mg/kg in CLARITY Extension (the CC7 group). In each treatment group, EDSS scores at 6-month intervals, EDSS score improvement/worsening each year, and time to 3- and 6-month confirmed EDSS progression were assessed from CLARITY baseline over 5 years of follow-up (including a variable bridging interval between studies). All analyses are descriptive, and no statistical comparisons were performed for between-treatment group differences. RESULTS: The median (95% confidence interval [CI]) EDSS score for patients in the CP3.5 group at 5 years was 2.5 (2.0-3.5) compared with 3.0 (2.5-3.5) at baseline. In the CC7 group, median EDSS score (95% CI) at 5 years was 2.0 (2.0-3.0) compared with 2.5 (2.5-3.0) at baseline. During year 5 for the CP3.5 group, and based on changes in minimum score each year, EDSS score stability was observed in 53.9% of patients, improvement in 21.3%, and worsening in 24.7%. In the CC7 group, EDSS score remained stable in 66.1%, improved in 18.1%, and worsened in 15.8% of patients. Over 70% of patients in both treatment groups did not show 3- or 6-month confirmed EDSS progression at 5 years from CLARITY baseline. CONCLUSIONS: These findings confirm long-term beneficial effects on disability afforded by either the recommended dose of cladribine tablets over 4 years (cumulative dose, 3.5 mg/kg) or a higher cumulative dose. TRIAL REGISTRATION: ClinicalTrials.gov NCT00213135 (CLARITY); NCT00641537 (CLARITY Extension).

COVID-19 in Patients With Neuromyelitis Optica Spectrum Disorders and Myelin Oligodendrocyte Glycoprotein Antibody Disease in North America: From the COViMS Registry.

BACKGROUND AND OBJECTIVE: To describe the impact of coronavirus disease 2019 (COVID-19) on people with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD). METHODS: The COVID-19 Infections in Multiple Sclerosis (MS) and Related Diseases (COViMS) Registry collected data on North American patients with MS and related diseases with laboratory-positive or highly suspected SARS-CoV-2 infection. Deidentified data were entered into a web-based registry by health care providers. Data were analyzed using t-tests, Pearson χ2 tests, or Fisher exact tests for categorical variables. Univariate logistic regression models examined effects of risk factors and COVID-19 clinical severity. RESULTS: As of June 7, 2021, 77 patients with NMOSD and 20 patients with MOGAD were reported in the COViMS Registry. Most patients with NMOSD were laboratory positive for SARS-CoV-2 and taking rituximab at the time of COVID-19 diagnosis. Most patients with NMOSD were not hospitalized (64.9% [95% CI: 53.2%-75.5%]), whereas 15.6% (95% CI: 8.3%-25.6%) were hospitalized only, 9.1% (95% CI: 3.7%-17.8%) were admitted to the ICU and/or ventilated, and 10.4% (95% CI: 4.6%-19.5%) died. In patients with NMOSD, having a comorbidity was the sole factor identified for poorer COVID-19 outcome (OR = 6.0, 95% CI: 1.79-19.98). Most patients with MOGAD were laboratory positive for SARS-CoV-2, and almost half were taking rituximab. Among patients with MOGAD, 75.0% were not hospitalized, and no deaths were recorded; no factors were different between those not hospitalized and those hospitalized, admitted to the ICU, or ventilated. DISCUSSION: Among the reported patients with NMOSD, a high mortality rate was observed, and the presence of comorbid conditions was associated with worse COVID-19 outcome. There were no deaths reported in the patients with MOGAD, although these observations are limited due to small sample size.

Expert Perspectives on COVID-19 Vaccination for People Living with Multiple Sclerosis.

COVID-19 vaccines are safe for people living with MS on or off disease-modifying therapies and are important for the prevention of COVID-19. Antibody responses for individuals on certain DMTs may be diminished, however, T-cell responses may be preserved in those individuals. Data are lacking regarding optimal timing of vaccinations, and delaying disease-modifying therapies may increase the risk of disease activity and progression. In this perspective podcast, the authors recommend COVID-19 vaccination as soon as possible, regardless of timing considerations, in most cases.

Longitudinal Study of Retinal Structure, Vascular, and Neuronal Function in Patients With Relapsing-Remitting Multiple Sclerosis: 1-Year Follow-Up.

Objective: The purpose of this study was to quantify retinal structural, vascular, and functional changes in patients with relapsing-remitting multiple sclerosis (RRMS) over 1 year. Methods: Eighty-eight eyes of 44 patients with RRMS underwent assessments of low contrast letter acuity (LCLA), retinal ganglion cell function detected by the steady-state pattern electroretinogram (PERG), axonal microstructural integrity measured as birefringence, intraretinal layer thicknesses by ultra-high-resolution optical coherence tomography (OCT), volumetric vessel density (VVD) by OCT angiography, and retinal tissue perfusion (RTP) by the Retinal Function Imager (RFI). All measurements were performed at baseline and 1-year follow-up. The impacts of disease activities and a history of optic neuritis (ON) were analyzed. Results: Compared to baseline, there were no significant differences in all variables (P > 0.05), except for the axonal birefringence and RTP. The birefringence's of the retinal fiber layer at the temporal and superior quadrants was significantly decreased (P < 0.05), whereas RTP was significantly increased (P < 0.05). In the subgroup with ON, significantly longer PERG latency and decreased VVD were observed at follow-up (P < 0.05). In patients with improved LCLA, significantly increased RTP and decreased VVD (P < 0.05) were also observed. Conclusions: This is the first longitudinal study that assessed the RTP and VVD, along with other retinal structural and functional parameters in MS. The recovery of retinal vascular function occurred with the improved LCLA, suggesting that these measurements may be associated with disease progression. Translational Relevance: The retinal microvascular changes could be potential biomarkers for monitoring therapeutic efficacy in MS.

Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis.

Importance: Emergence of SARS-CoV-2 causing COVID-19 prompted the need to gather information on clinical outcomes and risk factors associated with morbidity and mortality in patients with multiple sclerosis (MS) and concomitant SARS-CoV-2 infections. Objective: To examine outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS. Design, Setting, and Participants: This analysis used deidentified, cross-sectional data on patients with MS and SARS-CoV-2 infection reported by health care professionals in North American academic and community practices between April 1, 2020, and December 12, 2020, in the COVID-19 Infections in MS Registry. Health care professionals were asked to report patients after a minimum of 7 days from initial symptom onset and after sufficient time had passed to observe the COVID-19 disease course through resolution of acute illness or death. Data collection began April 1, 2020, and is ongoing. Exposures: Laboratory-positive SARS-CoV-2 infection or highly suspected COVID-19. Main Outcomes and Measures: Clinical outcome with 4 levels of increasing severity: not hospitalized, hospitalization only, admission to the intensive care unit and/or required ventilator support, and death. Results: Of 1626 patients, most had laboratory-positive SARS-CoV-2 infection (1345 [82.7%]), were female (1202 [74.0%]), and had relapsing-remitting MS (1255 [80.4%]). A total of 996 patients (61.5%) were non-Hispanic White, 337 (20.8%) were Black, and 190 (11.7%) were Hispanic/Latinx. The mean (SD) age was 47.7 (13.2) years, and 797 (49.5%) had 1 or more comorbidity. The overall mortality rate was 3.3% (95% CI, 2.5%-4.3%). Ambulatory disability and older age were each independently associated with increased odds of all clinical severity levels compared with those not hospitalized after adjusting for other risk factors (nonambulatory: hospitalization only, odds ratio [OR], 2.8 [95% CI, 1.6-4.8]; intensive care unit/required ventilator support, OR, 3.5 [95% CI, 1.6-7.8]; death, OR, 25.4 [95% CI, 9.3-69.1]; age [every 10 years]: hospitalization only, OR, 1.3 [95% CI, 1.1-1.6]; intensive care unit/required ventilator support, OR, 1.3 [95% CI, 0.99-1.7]; death, OR, 1.8 [95% CI, 1.2-2.6]). Conclusions and Relevance: In this registry-based cross-sectional study, increased disability was independently associated with worse clinical severity including death from COVID-19. Other risk factors for worse outcomes included older age, Black race, cardiovascular comorbidities, and recent treatment with corticosteroids. Knowledge of these risk factors may improve the treatment of patients with MS and COVID-19 by helping clinicians identify patients requiring more intense monitoring or COVID-19 treatment.

Increased multiple sclerosis disease activity in patients transitioned from fingolimod to dimethyl fumarate: a case series.

BACKGROUND: Fingolimod is a S1P1 receptor modulator that prevents activated lymphocyte egress from lymphoid tissues causing lymphopenia, mainly affecting CD4+ T lymphocytes. Withdrawal from fingolimod can be followed by severe disease reactivation, and this coincides with return of autoreactive lymphocytes into circulation. The CD8+ T cytotoxic population returns prior to the regulatory CD4+ T lymphocytes leading to a state of dysregulation, which may contribute to the rebound and severity of clinical relapses. On the other hand, dimethyl fumarate (DMF) preferentially reduces CD8+ T lymphocytes, has the same efficacy as fingolimod, and therefore, was expected to be a suitable oral alternative to reduce the rebound associated with fingolimod withdrawal. CASE PRESENTATION: We present six patients with relapsing-remitting MS who developed an unexpected increase in disease activity after transitioning from fingolimod to DMF. All patients were clinically and radiologically stable on fingolimod for at least 1 year. The switch in therapy was due to significantly low CD4+ T lymphocyte count ≤65 cells/ul (normal range 490-1740 cells/ul), after discussing the results with the patients and the potential risk for opportunistic infections including cryptococcal infections. DMF was introduced following a washout period of 5 to 11 weeks to allow reconstitution of the immune system and for the absolute lymphocyte count to reach ≥500 cells/ul. Every patient who experienced a relapse had several enhancing lesions in the brain and/or spinal cord between 12 to 23 weeks after cessation of fingolimod and 1 to 18 weeks after starting DMF. All relapses were treated with intravenous methylprednisolone with good clinical responses. CONCLUSION: The anticipated beneficial response of DMF treatment to mitigate rebound after fingolimod therapy cessation was not observed. Our patients experienced rebound disease despite being on treatment with DMF. Additional studies are necessary to understand which treatments are most effective to transition to after discontinuing fingolimod.

Physician Compensation in the United States - Through the Lens of the MS Neurologist.

PURPOSE OF REVIEW: To explore the elements that are typically considered when determining physician compensation in the United States and to examine if the compensation of neurologists with expertise in multiple sclerosis (MS) care is commensurate with that for other neurological specialists and medical specialists that also employ complex therapies, e.g., oncology. RECENT FINDINGS: The complexity in the diagnosis and management of MS requires increasing specialization. Additionally, changing models for the delivery of MS care has resulted in the MS neurologist generating significant contribution margins. In fact, the revenue to compensation ratio for the MS neurologist may be significantly higher than that of any other discipline in neuroscience service lines. However, while the contribution margin is often a key justification of compensation of interventional and intensive care practitioners in neuroscience service lines, it is generally not considered in the MS neurologist's compensation. Compensation models for MS neurologists typically depend heavily on the absolute number of relative value units associated with evaluation and management (E&M) codes making other fields of neurology financially more attractive to trainees. SUMMARY: In considering the shortage of MS specialists, the demands of their discipline, and the revenue to compensation ratios, the MS neurologist is significantly undercompensated relative to other neurological specialists and to physicians in other disciplines. Compensating the MS neurologist appropriately and supporting the necessary infrastructure for MS care will likely attract more trainees to this discipline and help reverse the current scarcity of MS neurologists in the United States.

Development of SARS-CoV-2 IgM and IgG antibodies in a relapsing multiple sclerosis patient on ofatumumab.

We report the case of a MS patient on subcutaneous ofatumumab who became infected with SARS-CoV-2 and remained asymptomatic while developing antiviral IgM and IgG antibodies. The patient was B-cell depleted with normal serum immunoglobulin levels. Anti-SARS-CoV-2 IgG antibodies remained positive three months after the initial infection. These findings suggest that a MS patient treated with ofatumumab may be able to mount an effective humoral response to SARS-CoV-2 infection and probably to COVID-19 vaccines as well. Further research will be necessary to evaluate the humoral response of MS patients on ofatumumab to SARS-CoV-2 infection and COVID-19 vaccines.

The North American Registry for Care and Research in Multiple Sclerosis (NARCRMS).

Although many regional multiple sclerosis (MS) databases existed in the United States and Canada, there was no single clinician-derived registry that examined this disease as a group across the North American continent. This distinction is important because information that results from such a database can potentially give perspectives about MS that cannot be derived from any single regional registry. A partnership was forged between the pharmaceutical industry and the Consortium of Multiple Sclerosis Centers (CMSC) to create a registry of patients with MS from Canada and the United States, including Puerto Rico. Case report forms were created to collect physician-derived information, and the Patient-Reported Outcomes Measurement Information System (PROMIS) was selected to capture patient-reported outcomes. As of November 2021, 754 of 1000 patients have been enrolled. Completion of recruitment is expected by the end of 2021. Twenty-five centers are participating, with an expected total of 30, including five centers from Canada. Clinical status, health economic outcomes, magnetic resonance images, and, soon, biomarkers relevant to understanding relapses and progression are collected. The short-term goal is to understand and better treat MS disease progression, and the long-term goal is its prevention. The North American Registry for Care and Research in Multiple Sclerosis (NARCRMS) is one of few clinician/patient-generated registries that examines MS across North America, including Puerto Rico. Information derived from the natural history studies should help physicians, the pharmaceutical industry, and regulatory bodies understand MS better and improve quality of life for patients with MS worldwide.