Clinical characteristics of patients with myelin oligodendrocyte glycoprotein antibodies.

PURPOSE OF REVIEW: The clinical landscape associated to myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) has undergone a remarkable transformation over the past two decades, primarily driven by advancements in antibody detection techniques that have enhanced both the specificity and sensitivity of assays, enabling the identification of novel clinical phenotypes. RECENT FINDINGS: Recent pivotal research publications, comprehensive reviews from established research groups, and most notably the first proposed international criteria for MOG-Ab associated disease (MOGAD) have substantially enriched our understanding of the clinical features associated with MOG-Ab. This review presents a comprehensive overview of the clinical characteristics of patients with MOG-Ab, systematically examining each core clinical syndrome defined by the proposed international MOGAD criteria. We incorporated recent insights and discussed potential challenges in applying these criteria across diverse clinical scenarios. SUMMARY: The proposed international MOGAD criteria provide a comprehensive, homogeneous, and specific framework for characterizing the clinical features of patients with MOG-Ab, encompassing both paediatric and adult populations. In the future, the widespread adoption of specific and reliable assays for MOG-Ab detection, complemented by the development of surrogate fluid and imaging markers, holds promise for better characterizing atypical presentations, only-cerebrospinal fluid positivity and the MOGAD "seronegative" situations.

Clinical correlates of respiratory disorders in patients with severe multiple sclerosis: A cross-sectional cohort.

BACKGROUND: Respiratory disorders remain incompletely described in multiple sclerosis (MS), even though they are a frequent cause of death. METHODS: The objective was to describe respiratory disorders in MS patients with Expanded Disability Status Score (EDSS) ⩾ 6.5. Diaphragm dysfunction was defined by at least two of the seven criteria: clinical signs, inspiratory recruitment of neck muscles during wakefulness, reduced upright vital capacity (VC) < 80%, upright-to-supine VC ⩾ 15% of upright VC, decrease in Maximal Inspiratory Pressure < 60%, phasic activation of inspiratory neck muscles during sleep, and opposition of thoracic and abdominal movements during sleep. Cough weakness was defined by a peak cough flow < 270 L/min and/or need for cough assist. Sleep apnea syndrome was defined by an apnea-hypopnea index ⩾ 15. RESULTS: Notably, 71 MS patients were included: median age 54 [48, 61] years; median disease duration 21.4 [16.0, 31.4] years. Of these, 52 patients had one or more respiratory disorders; diaphragm dysfunction was the most frequent (n = 34). Patients with diaphragm dysfunction and cough weakness were more disabled. The fatigue score and the cognitive evaluations did not differ between the groups. Five patients required non-invasive ventilation. CONCLUSION: Respiratory disorders are frequent in severe MS, mostly diaphragm dysfunction. Of interest, instrumental interventions are available to address these disorders.

Evidence of disease activity during pregnancy and post-partum in MS patients treated with high-efficacy therapies.

BACKGROUND: Multiple sclerosis (MS) predominantly affects women of childbearing age. Due to the risk of teratogenicity, women with active multiple sclerosis (MS) who require high-efficacy therapies (HET) may need to discontinue treatment during pregnancy. Fingolimod and Natalizumab withdrawal increases the risk of disease reactivation, a risk not commonly associated with anti-CD20 therapies. However, comparative data are limited during pregnancy and post-partum. Our aim was to compare evidence of disease activity during pregnancy and post-partum in women treated with HET (anti-CD20 therapies, Natalizumab or Fingolimod) before conception, whether or not exposed during pregnancy. METHODS: In this single-center retrospective study, we included consecutive pregnancies of relapsing-remitting MS patients and classified them in three groups according to the last HET used before conception: « anti-CD20 ¼ « Natalizumab (NTZ) ¼ and « Fingolimod (FGD) ¼. The main outcome was annualized relapse rate (ARR) during pregnancy and post-partum. RESULTS: We included 66 pregnancies: 21, 24 and 21 in anti-CD20, NTZ and FGD groups respectively. Overall, mean ARR (SD) increased from 0.36 (0.6) during the preconception year to 0.60 (1.3) during pregnancy and to 1.03 (2.0) in the first 3 months post-partum. Mean ARR in anti-CD20 group (0.09 (0.3)) during pregnancy and the first 3 months post-partum was lower compared with NTZ (0.48 (0.6); p = 0,09) and FGD (1.50 (1.8); p = 0.001) groups. Proportion of pregnancies with radiological activity during pregnancy and post-partum in anti-CD20 group (5.2 %) was lower compared with NTZ (63.1 %; p < 0.001) and FGD (72.2 %; p < 0.001) groups. There was no significant difference in the evolution of EDSS score from conception to post-partum between each group (p = 0.75). CONCLUSION: Evidence of disease activity was significantly lower in patients exposed to anti-CD20 therapies before conception. This study suggests that use of anti-CD20 therapies is an efficient option to prevent disease reactivation during pregnancy and post-partum.

High-Efficacy Therapy Discontinuation vs Continuation in Patients 50 Years and Older With Nonactive MS.

Importance: A recent randomized clinical trial concluded that discontinuing medium-efficacy therapy might be a reasonable option for older patients with nonactive multiple sclerosis (MS), but there is a lack of data on discontinuing high-efficacy therapy (HET). In younger patients, the discontinuation of natalizumab and fingolimod is associated with a risk of rebound of disease activity. Objective: To determine whether discontinuing HET in patients 50 years and older with nonactive MS is associated with an increased risk of relapse compared with continuing HET. Design, Setting, and Participants: This observational cohort study used data from 38 referral centers from the French MS registry (Observatoire Français de la Sclérose en Plaques [OFSEP] database). Among 84704 patients in the database, data were extracted for 1857 patients 50 years and older with relapsing-remitting MS treated by HET and with no relapse or magnetic resonance imaging activity for at least 2 years. After verification of the medical records, 1620 patients were classified as having discontinued HET or having remained taking treatment and were matched 1:1 using a dynamic propensity score (including age, sex, disease phenotype, disability, treatment of interest, and time since last inflammatory activity). Patients were included from February 2008 to November 2021, with a mean (SD) follow-up of 5.1 (2.9) years. Data were extracted in June 2022. Exposures: Natalizumab, fingolimod, rituximab, and ocrelizumab. Main Outcomes and Measures: Time to first relapse. Results: Of 1620 included patients, 1175 (72.5%) were female, and the mean (SD) age was 54.7 (4.8) years. Among the 1452 in the HET continuation group and 168 in the HET discontinuation group, 154 patients in each group were matched using propensity scores (mean [SD] age, 57.7 [5.5] years; mean [SD] delay since the last inflammatory activity, 5.6 [3.8] years; mean [SD] follow-up duration after propensity score matching, 2.5 [2.1] years). Time to first relapse was significantly reduced in the HET discontinuation group compared with the HET continuation group (hazard ratio, 4.1; 95% CI, 2.0-8.5; P < .001) but differed between HETs, with a hazard ratio of 7.2 (95% CI, 2.1-24.5; P = .001) for natalizumab, 4.5 (95% CI, 1.3-15.5; P = .02) for fingolimod, and 1.1 (95% CI, 0.3-4.8; P = .85) for anti-CD20 therapy. Conclusion and Relevance: As in younger patients, in patients 50 years and older with nonactive MS, the risk of relapse increased significantly after stopping HETs that impact immune cell trafficking (natalizumab and fingolimod). There was no significant increase in risk after stopping HETs that deplete B-cells (anti-CD20 therapy). This result may inform decisions about stopping HETs in clinical practice.

Highly Effective Therapies as First-Line Treatment for Pediatric-Onset Multiple Sclerosis.

Importance: Moderately effective therapies (METs) have been the main treatment in pediatric-onset multiple sclerosis (POMS) for years. Despite the expanding use of highly effective therapies (HETs), treatment strategies for POMS still lack consensus. Objective: To assess the real-world association of HET as an index treatment compared with MET with disease activity. Design, Setting, and Participants: This was a retrospective cohort study conducted from January 1, 2010, to December 8, 2022, until the last recorded visit. The median follow-up was 5.8 years. A total of 36 French MS centers participated in the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. Of the total participants in OFSEP, only treatment-naive children with relapsing-remitting POMS who received a first HET or MET before adulthood and at least 1 follow-up clinical visit were included in the study. All eligible participants were included in the study, and none declined to participate. Exposure: HET or MET at treatment initiation. Main Outcomes and Measures: The primary outcome was the time to first relapse after treatment. Secondary outcomes were annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, time to Expanded Disability Status Scale (EDSS) progression, tertiary education attainment, and treatment safety/tolerability. An adapted statistical method was used to model the logarithm of event rate by penalized splines of time, allowing adjustment for effects of covariates that is sensitive to nonlinearity and interactions. Results: Of the 3841 children (5.2% of 74 367 total participants in OFSEP), 530 patients (mean [SD] age, 16.0 [1.8] years; 364 female [68.7%]) were included in the study. In study patients, both treatment strategies were associated with a reduced risk of first relapse within the first 2 years. HET dampened disease activity with a 54% reduction in first relapse risk (adjusted hazard ratio [HR], 0.46; 95% CI, 0.31-0.67; P < .001) sustained over 5 years, confirmed on MRI activity (adjusted odds ratio [OR], 0.34; 95% CI, 0.18-0.66; P = .001), and with a better tolerability pattern than MET. The risk of discontinuation at 2 years was 6 times higher with MET (HR, 5.97; 95% CI, 2.92-12.20). The primary reasons for treatment discontinuation were lack of efficacy and intolerance. Index treatment was not associated with EDSS progression or tertiary education attainment (adjusted OR, 0.51; 95% CI, 0.24-1.10; P = .09). Conclusions and Relevance: Results of this cohort study suggest that compared with MET, initial HET in POMS was associated with a reduction in the risk of first relapse with an optimal outcome within the first 2 years and was associated with a lower rate of treatment switching and a better midterm tolerance in children. These findings suggest prioritizing initial HET in POMS, although long-term safety studies are needed.

Impact of Immune Checkpoint Inhibitors on the Course of Multiple Sclerosis.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are increasingly used in cancer treatment. Their mechanism of action raises the question of possible exacerbation of preexisting multiple sclerosis (MS). The aim of our study was to assess the risk of increased MS activity, defined by the occurrence of a relapse and/or a new MRI lesion, after ICI initiation. METHODS: This French multicentric study collected retrospective and prospective data on patients with MS treated with ICIs after a cancer diagnosis. RESULTS: We identified 18 patients with a median age of 48 years. Three of them (17%), all aged 50 years or younger, with a relapsing-remitting course, showed clinical and/or radiologic signs of MS activity 3 to 6 months after ICI initiation. They had stopped disease-modifying treatment (DMT) several months earlier, at the time of cancer diagnosis. Only one had both clinical and MRI activity, with mild severity and complete recovery. DISCUSSION: Our study suggests that the overall risk of MS activity under ICI is low and could be mainly driven by DMT discontinuation, as in MS in general. Although larger studies are needed for better risk assessment in younger patients with more active disease, ICI should be considered when needed in patients with MS.

Cancer and multiple sclerosis: 2023 recommendations from the French Multiple Sclerosis Society.

BACKGROUND: Epidemiological data reveal that 45% of persons with multiple sclerosis (PwMS) in France are more than 50 years. This population more than 50 is more susceptible to cancer, and this risk may be increased by frequent use of immunosuppressive drugs. Consequently, concerns have arisen about the potential increased risk of cancer in PwMS and how patients should be screened and managed in terms of cancer risk. OBJECTIVE: To develop evidence-based recommendations to manage the coexistence of cancer and multiple sclerosis (MS). METHODS: The French Group for Recommendations in MS collected articles from PubMed and university databases covering the period January 1975 through June 2022. The RAND/UCLA method was employed to achieve formal consensus. MS experts comprehensively reviewed the full-text articles and developed the initial recommendations. A group of multidisciplinary health care specialists then validated the final proposal. RESULTS: Five key questions were addressed, encompassing various topics such as cancer screening before or after initiating a disease-modifying therapy (DMT), appropriate management of MS in the context of cancer, recommended follow-up for cancer in patients receiving a DMT, and the potential reintroduction of a DMT after initial cancer treatment. A strong consensus was reached for all 31 recommendations. CONCLUSION: These recommendations propose a strategic approach to managing cancer risk in PwMS.

The Response Study: A French registry on pregnancy in women with MS and related disorders and their children up to 6 years-Protocol, recruitment status, and baseline characteristics.

BACKGROUND: Counseling on pregnancy is still challenging, particularly regarding the use of disease-modifying treatments (DMTs). We are lacking long-term outcomes in children exposed to DMTs. OBJECTIVES: This study aimed to set up a French pregnancy registry for women with multiple sclerosis (MS) and related disorders nested within the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. METHODS: Prospective, observational, multicentric, epidemiological study in France. Neurological visits are organized according to routine practice. Data are collected on the OFSEP minimal datasheet. Auto-questionnaires on pregnancy are completed by patients at Months 5-6 and 8 during pregnancy, and Months 3, 6, and 12 postpartum. A specific survey on analgesia is completed by anesthesiologists. Pediatric data are collected from the child's health book, where visits on Day 8, Month 9, and 24 are mandatory. Parents complete neurodevelopmental questionnaires at Year 1, Years 2 and 6. RESULTS: The RESPONSE study started in August 2019. On 7 April 2023, 515 women were included. Baseline demographics are presented. CONCLUSIONS: RESPONSE will provide rich information on the global management of pregnancy in France and prospective data on children until the age of 6 years, exposed or not to a DMT, including data on neurodevelopment that can be compared to the general population. STUDY FUNDING: EDMUS and ARSEP Foundation, Biogen, Roche.

COVID-19 outcomes in patients with multiple sclerosis: Understanding changes from 2020 to 2022.

BACKGROUND: Epidemiologic studies on coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (pwMS) have focused on the first waves of the pandemic until early 2021. OBJECTIVES: We aimed to extend these data from the onset of the pandemic to the global coverage by vaccination in summer 2022. METHODS: This retrospective, multicenter observational study analyzed COVISEP registry data on reported COVID-19 cases in pwMS between January 2020 and July 2022. Severe COVID-19 was defined as hospitalization or higher severity. RESULTS: Among 2584 pwMS with confirmed/highly suspected COVID-19, severe infection rates declined from 14.6% preomicron wave to 5.7% during omicron wave (p < 0.001). Multivariate analysis identified age (odds ratio (OR) = 1.43, 95% confidence interval (CI) = [1.25-1.64] per 10 years), male sex (OR = 2.01, 95% CI = [1.51-2.67]), obesity (OR = 2.36, 95% CI = [1.52-3.68]), cardiac comorbidities (OR = 2.36, 95% CI = [1.46-3.83]), higher Expanded Disability Status Scale (EDSS) scores (OR = 2.09, 95% CI = [1.43-3.06] for EDSS 3-5.5 and OR = 4.53, 95% CI = [3.04-6.75] for EDSS ⩾6), and anti-CD20 therapies (OR = 2.67, 95% CI = [1.85-3.87]) as risk factors for COVID-19 severity. Vaccinated individuals experienced less severe COVID-19, whether on (risk ratio (RR) = 0.64, 95% CI = [0.60-0.69]) or off (RR = 0.32, 95% CI = [0.30-0.33]) anti-CD20. DISCUSSION: In pwMS, consistent risk factors were anti-CD20 therapies and neurological disability, emerging as vital drivers of COVID-19 severity regardless of wave, period, or vaccination status.

Longitudinally extensive posterolateral myelitis revealing invasive CNS aspergillosis in an immunocompetent patient.

BACKGROUND: Fungal infections of the central nervous system usually affect immunocompromised patients. Primary Aspergillus myelitis has never been described. REPORT: A 45-year-old immunocompetent male with subacute paraplegia was treated for inflammatory myelitis before clinical deterioration requiring mechanical ventilation. Purulent meningitis preceded the formation of a paraspinal nodule biopsied by neurosurgery. Histopathological analysis revealed the presence of fungal hyphae, and polymerase chain reaction was positive for Aspergillus fumigatus. No cause of immunodeficiency was identified in this patient. DISCUSSION: Primary Aspergillus myelitis may be confused with inflammatory myelitis and should be considered even in the absence of apparent immunosuppression.

Risk factors and prognosis of orotracheal intubation in aquaporin-4-IgG neuromyelitis optica spectrum disorder attacks.

BACKGROUND: Aquaporin-4 immunoglobulin G Neuro Myelitis Optica spectrum disorders attacks (NMOSD-AQP4-IgG+ attacks) can cause respiratory failure requiring orotracheal intubation (OTI), but the risk factors and outcomes of OTI during attacks remain unclear. Our primary objective was to identify the clinical and radiological risk factors for OTI in NMOSD-AQP4-IgG+ attacks. As a secondary objective, we aimed to evaluate the prognosis of OTI-attacks. METHODS: We retrospectively analyzed NMOSD-AQP4-IgG+ attacks at the Pitié-Salpêtrière Hospital (Jan 2010-Jan 2021), excluding isolated optic neuritis. The primary outcome was the need for OTI due to neurological dysfunction an attack (OTI-attack). The secondary outcome was attack's poor recovery after 12 months, defined as a modified Rankin score (mRS) > 2 in patients with an initial mRS ≤ 2, or an increase ≥ 1 point in mRS in other patients. Analyses were performed using a binomial generalized linear mixed model, with a random intercept for the patient ID to account for within-patient correlations. RESULTS: Seventy-three attacks in 44 patients NMOSD-AQP4-IgG+ were analyzed. Of 73 attacks, 8 (11%) required OTI during the attack, related to acute restrictive respiratory failure (n = 7) and/or severe swallowing disorder (n = 2). None of the OTI-attacks occurred in patients previously treated with active disease-modifying treatment (DMT), while 36 (55.4%) of the non-OTI-attacks occurred in patients who were already on active DMT. On admission, OTI-attacks were more likely to have upper limbs motor paresis of (75.0% versus 29.2%, p = 0.366) and dyspnea (3 [50.0%] versus 4 [6.6%], p = 0.002) compared to non-OTI-attacks. MRI analysis showed that OTI-attacks had edematous lesions in the cervical spinal cord, mainly at levels C1 (75% versus 0% in non-OTI-attacks), C2 (75% versus 1.9%), C3 (62.5% versus 1.9%), and C4 and C5 levels (50% versus to 3.9%). One OTI-attack resulted in the death of one patient. Five patients with OTI-attack had mRS ≤ 2 one year after OTI-attack. Two (25%) OTI-attacks had poor recovery compared to 15 (24.2%) non-OTI-attacks (p = 0.468). CONCLUSION: OTI-attacks occurred in untreated NMOSD-AQP4-IgG+ patients and were associated with edematous upper cervical lesions. The prognosis of these attacks may be favorable, and warrant maximal medical and supportive treatment. Trial registration This was a retrospective observational monocentric cohort study nested in the NOMADMUS cohort (ClinicalTrials.gov Identifier: NCT02850705).

Control of disease activity with large extended-interval dosing of rituximab/ocrelizumab in highly active pediatric multiple sclerosis.

Recent studies in adults suggested that extended-interval dosing of rituximab/ocrelizumab (RTX/OCR) larger than 12 months was safe and could improve safety. This was an observational cohort study of very active pediatric-onset multiple sclerosis (PoMS) (median (range) age, 16 (12-17) years) treated with RTX/OCR with 6 month standard-interval dosing (n = 9) or early extended-interval dosing (n = 12, median (range) interval 18 months (12-25)). Within a median (range) follow-up of 31 (12-63) months after RTX/OCR onset, one patient (standard-interval) experienced relapse and no patient showed disability worsening or new T2-weighted lesions. This study suggests that the effectiveness of RTX/OCR is maintained with a median extended-interval dosing of 18 months in patients with very active PoMS.

Recurrence of severe symptomatic late-onset neutropenia on ocrelizumab.

BACKGROUND: Late-onset neutropenia (LON), defined as an absolute neutrophil count (ANC) < 1500/mm3 that develops between 4 weeks and 6 months after the last drug administration, is a rare side effect of anti-CD20 drugs including ocrelizumab. Although continuation of ocrelizumab after LON is not contraindicated, the risk of LON recurrence is not well known. CASES: We report three cases of recurrent symptomatic agranulocytosis (ANC < 500/mm3) occurring under ocrelizumab. CONCLUSION: Given the risk of recurrence of symptomatic agranulocytosis and the availability of other treatments, a therapeutic switch may be discussed after the first episode of LON.

Is vaccine response to SARS-CoV-2 preserved after switching to anti-CD20 therapies in patients with multiple sclerosis or related disorders?

BACKGROUND: Although vaccination against SARS-CoV-2 is recommended prior to introducing anti-CD20 therapies, limited data are available regarding the evolution of post-vaccinal immunity. METHODS: This retrospective study compared anti-Spike antibody titres at 6 and 12 months from SARS-CoV-2 vaccination between patients vaccinated before switching to anti-CD20 ('Switch') and two control groups: (1) patients vaccinated under disease-modifying therapies (DMTs) other than fingolimod and anti-CD20 ('Other DMTs'); (2) patients vaccinated on anti-CD20 ('Anti-CD20'). Anti-Spike-specific T-cell responses were compared between 'Switch' and 'Anti-CD20' groups. RESULTS: Fifty-three patients were included in the 'Switch' group, 54 in the 'Other DMTs' group and 141 in the 'Anti-CD20' group. At 6 months, in the subset of patients who received a booster dose, the 'Switch' group had lower anti-Spike titres compared with the 'Other DMTs' group (median 241.0 IQR (88.0; 504.0) BAU/mL vs 2034 (1155; 4634) BAU/mL, p<0.001), and less patients in the 'Switch' group reached the protective threshold of 264 BAU/mL. The 'Switch' group had higher anti-Spike titres than the 'Anti-CD20' group (7.5 (0.0; 62.1) BAU/mL, p=0.001). Anti-Spike titres were not different between the 'Switch' and 'Other DMTs' groups before booster administration. These results were similar at 12 months. Spike-specific T-cell positivity was similar between the 'Switch' and 'Anti-CD20' groups at 6 and 12 months (60.4% vs 61.0%, p=0.53, and 79.4% vs 87.5%, p=0.31, respectively). CONCLUSIONS: Despite a primary vaccination performed before the first anti-CD20 cycle, our results suggest weaker immune responses at 6 and 12 months and decreased booster efficacy after introducing anti-CD20. Patients vaccinated prior to anti-CD20 introduction might falsely be considered as fully protected by vaccination.

Rituximab De-escalation in Patients With Neuromyelitis Optica Spectrum Disorder.

BACKGROUND AND OBJECTIVES: Exit strategies such as de-escalations have not been evaluated for rituximab in patients with neuromyelitis optica spectrum disorder (NMOSD). We hypothesized that they are associated with disease reactivations and aimed to estimate this risk. METHODS: We describe a case series of real-world de-escalations from the French NMOSD registry (NOMADMUS). All patients met the 2015 International Panel for NMO Diagnosis (IPND) diagnostic criteria for NMOSD. A computerized screening of the registry extracted patients with rituximab de-escalations and at least 12 months of subsequent follow-up. We searched for 7 de-escalation regimens: scheduled discontinuations or switches to an oral treatment after single infusion cycles, scheduled discontinuations or switches to an oral treatment after periodic infusions, de-escalations before pregnancies, de-escalations after tolerance issues, and increased infusion intervals. Rituximab discontinuations motivated by inefficacy or for unknown purposes were excluded. The primary outcome was the absolute risk of NMOSD reactivation (one or more relapses) at 12 months. AQP4+ and AQP4- serotypes were analyzed separately. RESULTS: We identified 137 rituximab de-escalations between 2006 and 2019 that corresponded to a predefined group: 13 discontinuations after a single infusion cycle, 6 switches to an oral treatment after a single infusion cycle, 9 discontinuations after periodic infusions, 5 switches to an oral treatment after periodic infusions, 4 de-escalations before pregnancies, 9 de-escalations after tolerance issues, and 91 increased infusion intervals. No group remained relapse-free over the whole de-escalation follow-up (mean: 3.2 years; range: 0.79-9.5), except pregnancies in AQP+ patients. In all groups combined and within 12 months, reactivations occurred after 11/119 de-escalations in patients with AQP4+ NMOSD (9.2%, 95% CI [4.7-15.9]), from 0.69 to 10.0 months, and in 5/18 de-escalations in patients with AQP4- NMOSD (27.8%, 95% CI [9.7-53.5]), from 1.1 to 9.9 months. DISCUSSION: There is a risk of NMOSD reactivation whatever the rituximab de-escalation regimen. TRIAL REGISTRATION INFORMATION: Registered on ClinicalTrials.gov: NCT02850705. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that de-escalation of rituximab increases the probability of disease reactivation.

Association Between Anti-CD20 Therapies and COVID-19 Severity Among Patients With Relapsing-Remitting and Progressive Multiple Sclerosis.

Importance: In patients with multiple sclerosis (MS), factors associated with severe COVID-19 include anti-CD20 therapies and neurologic disability, but it is still unclear whether these 2 variables are independently associated with severe COVID-19 or whether the association depends on MS clinical course. Objective: To assess the association between anti-CD20 therapies and COVID-19 severity in patients with relapsing-remitting MS (RRMS) and progressive MS (PMS). Design, Setting, and Participants: This multicenter, retrospective cohort study used data from the COVISEP study, which included patients with MS and COVID-19 from February 1, 2020, to June 30, 2022, at 46 French MS expert centers, general hospitals, and private neurology practices. Eligible patients with RRMS were those treated with high-efficacy MS therapy (ie, anti-CD20, fingolimod, or natalizumab), and eligible patients with PMS were those younger than 70 years with an Expanded Disability Status Scale (EDSS) score of 8 or lower. Patients were monitored from COVID-19 symptom onset until recovery or death. Exposures: Current anti-CD20 therapy (ocrelizumab or rituximab). Main Outcomes and Measures: The main outcome was severe COVID-19 (ie, hospitalization with any mode of oxygenation or death). All analyses were conducted separately in patients with RRMS and PMS using propensity score-weighted logistic regression. Subgroup analyses were performed according to COVID-19 vaccine status, sex, EDSS score, and age. Results: A total of 1400 patients, 971 with RRMS (median age, 39.14 years [IQR, 31.38-46.80 years]; 737 [76.1%] female) and 429 with PMS (median age, 54.21 years [IQR, 48.42-60.14 years]; 250 [58.3%] female) were included in the study. A total of 418 patients with RRMS (43.0%) and 226 with PMS (52.7%) were treated with anti-CD20 therapies. In weighted analysis, 13.4% and 2.9% of patients with RRMS treated and not treated with anti-CD20 had severe COVID-19, respectively, and anti-CD20 treatment was associated with increased risk of severe COVID-19 (odds ratio [OR], 5.20; 95% CI, 2.78-9.71); this association persisted among vaccinated patients (7.0% vs 0.9%; OR, 8.85; 95% CI, 1.26-62.12). Among patients with PMS, 19.0% and 15.5% of patients treated and not treated with anti-CD20 had severe COVID-19, respectively, and there was no association between anti-CD20 treatment and severe COVID-19 (OR, 1.28; 95% CI, 0.76-2.16). In PMS subgroup analysis, anti-CD20 exposure interacted negatively with EDSS score (P = .009 for interaction) and age (P = .03 for interaction); anti-CD20 therapies were associated with risk of severe COVID-19 only in patients with less neurologic disability and younger patients with PMS. Conclusions and Relevance: In this cohort study, risk of severe COVID-19 was higher in patients with PMS than in those with RRMS. Use of anti-CD20 therapies was associated with an increased risk of severe COVID-19 among patients with RRMS. In patients with PMS, there was no association between anti-CD20 therapies and risk of severe COVID-19.

Relevance of kappa free light chains index in patients with aquaporin-4 or myelin-oligodendrocyte-glycoprotein antibodies.

BACKGROUND: The kappa free light chains index (κ-index) is increasing in importance as a fast, easy, cost-effective, and quantitative biomarker in multiple sclerosis (MS), which can replace cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCB) detection. In previous studies, controls often included mixed patients with several inflammatory central nervous system disorders. The aim of the present study was to assess the κ-index in patients with serum aquaporin-4 (AQP4)-IgG or myelin-oligodendrocyte-glycoprotein (MOG)-IgG. METHODS: We analyzed CSF/serum samples of patients with AQP4-IgG or MOG-Ig and evaluated distinct κ-index cut-offs. We described clinical and magnetic resonance imaging (MRI) features of patients with the highest κ-index values. RESULTS: In 11 patients with AQP4-IgG, median κ-index was 16.8 (range 0.2; 63) and 6/11 (54.5%) had κ-index >12. Among 42 patients with MOG-IgG, 2 had low positive MOG-IgG titers, were ultimately diagnosed with MS, and had a markedly increased κ-index (54.1 and 102.5 respectively). For the remaining 40 MOG-IgG-positive patients the median κ-index was 0.3 (range 0.1; 15.5). Some 6/40 (15%) and 1/40 (2.5%) patients had a κ-index >6 and >12, respectively. None fulfilled MRI dissemination in space and dissemination in time (DIS/DIT) criteria and the final diagnosis was MOG-IgG-associated disease (MOGAD) for these 40 patients. Four of the 40 (10%) MOG-IgG-positive patients had OCB. CONCLUSION: While a marked increase in κ-index could discriminate MS from MOGAD, a low κ-index threshold could lead to confusion between MS and MOGAD or AQP4 antibody-positive neuromyelitis optica spectrum disorder.

Treatments of paediatric multiple sclerosis: Efficacy and tolerance in a longitudinal follow-up study.

AIM: To compare the efficacy and safety of newer and/or second-line disease-modifying treatments (DMTs) with interferon beta-1a. METHOD: This observational retrospective study included patients younger than 18 years old in the French KIDBIOSEP cohort who had a diagnosis of relapsing multiple sclerosis between 2008 and 2019 and received at least one DMT. Primary outcome was the annualized relapse rate (ARR). Secondary outcomes were the risk of new T2 or gadolinium-enhanced lesions on brain MRI. RESULTS: Among 78 patients enrolled, 50 were exposed to interferon and 76 to newer DMTs. Mean ARR went from 1.65 during pre-treatment period to 0.45 with interferon (p < 0.001). Newer DMTs reduced ARR compared to interferon: fingolimod 0.27 (p = 0.013), teriflunomide 0.25 (p = 0.225), dimethyl-fumarate 0.14 (p = 0.045), natalizumab 0.03 (p = 0.007). Risk of new lesions on MRI was reduced with interferon compared to pre-treatment period; it decreased even more with newer DMTs for T2 lesions. Regarding risk of new gadolinium-enhanced lesions, the added value of new treatments compared to interferon was less obvious, except for natalizumab (p = 0.031). CONCLUSION: In this real-world setting, newer DMTs showed better efficacy than interferon beta-1a on ARR and risk of new T2 lesions, with a good safety profile. Natalizumab tend to emerge as the most effective treatment.

Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic.

The immune system plays a significant role in multiple sclerosis. While MS was historically thought to be T cell-mediated, multiple pieces of evidence now support the view that B cells are essential players in multiple sclerosis pathogenic processes. High-efficacy disease-modifying therapies that target the immune system have emerged over the past two decades. Anti-CD20 monoclonal antibodies selectively deplete CD20+ B and CD20+ T cells and efficiently suppress inflammatory disease activity. These monotherapies prevent relapses, reduce new or active magnetic resonance imaging brain lesions, and lessen disability progression in patients with relapsing multiple sclerosis. Rituximab, ocrelizumab, and ofatumumab are currently used in clinical practice, while phase III clinical trials for ublituximab have been recently completed. In this review, we compare the four anti-CD20 antibodies in terms of their mechanisms of action, routes of administration, immunological targets, and pharmacokinetic properties. A deeper understanding of the individual properties of these molecules in relation to their efficacy and safety profiles is critical for their use in clinical practice.