Active and non-active progression independent of relapse activity within the first 20 years of relapsing multiple sclerosis.

BACKGROUND: Progression independent of relapse activity (PIRA) has been described since the early stage of relapsing multiple sclerosis (RMS). However, little is known about the relation between PIRA and inflammatory activity that is particularly important at this stage of the disease. METHOD: We included 110 patients in a prospective study within 18 months of RMS onset. MRI examinations and clinical visits were scheduled on the same day for months 0, 6, 12, 24, 36, 60, 84, 120, 180 and 240. RESULTS: The mean (SD) age of patients was 30 (6.7) years at inclusion and median (range) follow-up 15 (9-20) years. Analysis of 1118 between-visit intervals revealed 93 confirmed disability accumulation events in 68 (62%) patients: 50 (54%) events related to relapse activity worsening and 43 (46%) PIRA events, including 17 (18%) with MRI activity. The risk of PIRA between two visits (stable event as the reference category) was associated with Expanded Disability Status Scale (EDSS) score (HR: 1.41; 95% CI: 1.18 to 1.69; p<0.001), disease duration (HR: 0.75; 95% CI: 0.62 to 0.90; p<0.005) and new lesions between the visits (HR: 1.09 per lesion; 95% CI: 1.01 to 1.17; p<0.05). As compared with PIRA events with MRI activity, PIRA events without such activity occurred in patients with more disability (mean EDSS score 3, p<0.05), longer disease duration (mean 11 years, p<0.001) and greater number of T2-weighted lesions (p<0.05). CONCLUSION: This study evidenced that inflammatory activity increases the risk of PIRA in early RMS, arguing that a significant part of PIRA is accessible to treatment targeting inflammation in these patients.

Effect of Prior Treatment With Fingolimod on Early and Late Response to Rituximab/Ocrelizumab in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Real-life studies noted that the risk of disease activity in multiple sclerosis (MS) after switching to rituximab (RTX) or ocrelizumab (OCR) may be unequal depending on prior disease-modifying therapy (DMT), with a higher risk associated with fingolimod (FING). METHODS: We performed a retrospective analysis of a structured prospective data collection including all consecutive patients with relapsing MS who were prescribed RTX/OCR in the MS center of Marseille. Cox proportional hazards models were applied to clinical and MRI outcomes. RESULTS: We included 321 patients with a median (interquartile range [IQR]) follow-up of 3.5 years (1.5-5) after RTX/OCR initiation. At the first RTX/OCR infusion, the mean (SD) age of patients was 37 (10) years, and the median (IQR) disease duration was 8 years (3-15): 68 patients did not receive treatment before RTX/OCR and 108 switched from FING, 47 from low efficacy therapy, and 98 from natalizumab. For statistical analysis, the group "FING" was divided into "short-FING" and "long-FING" groups according to the median value of the group's washout period (27 days). On Cox proportional hazards analysis, for only the "long-FING" group, the risk of relapse within the first 6 months of RTX/OCR was increased as compared with patients without previous DMT (hazard ratio [HR]: 8.78; 95% CI 1.72-44.86; p < 0.01). Previous DMT and washout period duration of FING had no effect on B-cell levels at 6 months. Beyond the first 6 months of RTX/OCR, age <40 years was associated with increased risk of relapse (HR: 3.93; 95% CI 1.30-11.89; p = 0.01), male sex with increased risk of new T2 lesions (HR: 2.26; 95% CI 1.08-4.74; p = 0.03), and EDSS ≥2 with increased risk of disability accumulation (HR: 3.01; 95% CI 1.34-6.74; p < 0.01). Previous DMT had no effect on the effectiveness of RTX/OCR beyond 6 months after initiation. DISCUSSION: For patients switching from FING to RTX/OCR, the risk of disease reactivation within the first 6 months of treatment was increased as compared with patients with other DMT or no previous DMT only when the washout period exceeded 26 days. Neither FING nor other previous DMT reduced the effectiveness of RTX/OCR beyond the first 6 months of treatment.

Factors affecting the topography of nitrous oxide-induced neurological complications.

BACKGROUND: The factors underlying the topography of nitrous oxide (N2O)-induced neurological complications are unknown. METHODS: We included all consecutive patients admitted to the university hospital of Marseille for N2O-induced neurological complications in a prospective observational study. Patients underwent neurological examination, spinal cord magnetic resonance imaging, and nerve conduction studies within the first 4 weeks after admission. RESULTS: In total, 61 patients were included: 45% with myeloneuropathy, 34% with isolated myelopathy, and 21% with isolated neuropathy. On multivariable analysis, the odds of myelopathy were associated with the amount of weekly N2O consumption (~600 g cylinder per week, odds ratio [OR] = 1.11, 95% confidence interval [CI] = 1.001-1.24). The extent of the myelopathy (number of vertebral segments) was correlated with the number of ~600-g cylinders consumed weekly (ρ = 0.40, p < 0.005). The odds of neuropathy were associated with the duration of consumption (per month; OR = 1.29, 95% CI = 1.05-1.58). Mean lower-limb motor nerve amplitude was correlated with the duration of consumption (in months; ρ = -0.34, p < 0.05). CONCLUSIONS: The odds of myelopathy increased with the amount of N2O consumption, and the odds of neuropathy increased with the duration of N2O exposure, which suggests distinct pathophysiological mechanisms underlying these two neurological complications.

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.

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.

Efficacy of Rituximab Outlasts B-Cell Repopulation in Multiple Sclerosis: Time to Rethink Dosing?

BACKGROUND AND OBJECTIVES: Patients with multiple sclerosis (PwMS) receiving extended dosing of rituximab (RTX) have exhibited no return of disease activity, which suggests that maintenance of deep depletion of circulating B cells is not necessary to maintain the efficacy of RTX in MS. METHODS: This was a prospective monocentric observational study including all consecutive PwMS who started or continued RTX after 2019, when the medical staff decided to extend the dosing interval up to 24 months for all patients. Circulating B-cell subsets were monitored regularly and systematically in case of relapse. The first extended interval was analyzed. RESULTS: We included 236 PwMS (81% with relapsing-remitting MS; mean [SD] age 43 [12] years; median [range] EDSS score 4 [0-8]; mean relapse rate during the year before RTX start 1.09 [0.99]; 41.5% with MRI activity). The median number of RTX infusions before extension was 4 (1-13). At the time of the analysis, the median delay in dosing was 17 months (8-39); the median proportion of circulating CD19+ B cells was 7% (0-25) of total lymphocytes and that of CD27+ memory B cells was 4% (0-16) of total B cells. The mean annual relapse rate did not differ before and after the extension: 0.03 (0.5) and 0.04 (0.15) (p = 0.51). Similarly, annual relapse rates did not differ before and after extension in patients with EDSS score ≤3 (n = 79) or disease duration ≤5 years (n = 71) at RTX onset. During the "extended dosing" period, MRI demonstrated no lesion accrual in 228 of the 236 patients (97%). Five patients experienced clinical relapse, which was confirmed by MRI. In these patients, the level of B-cell subset reconstitution at the time of the relapse did not differ from that for patients with the same extension window. DISCUSSION: The efficacy of RTX outlasted substantial reconstitution of circulating B cells in PwMS, which suggests that renewal of the immune system underlies the prolonged effect of RTX in MS. These findings suggest that extended interval dosing of RTX that leads to a significant reconstitution of circulating B cells is safe in PwMS, could reduce the risk of infection, and could improve vaccine efficacy.

Disease Evolution in Women With Highly Active MS Who Suspended Natalizumab During Pregnancy vs Rituximab/Ocrelizumab Before Conception.

BACKGROUND AND OBJECTIVES: In women with highly active multiple sclerosis (MS), suspending rituximab (RTX) for planning pregnancy is associated with low disease reactivation. Whether this strategy reduces the risk of disease reactivity as compared with suspending natalizumab (NTZ) 3 months after conception is unclear. METHODS: We retrospectively included women with MS followed in our department during pregnancy and 1 year after birth who suspended NTZ at the end of the first trimester (option mostly proposed before 2016) or suspended RTX/ocrelizumab (RTX/OCR) in the year before conception (option proposed since 2016). RESULTS: In women who suspended NTZ, 45 pregnancies resulted in 3 miscarriages and 42 live births, including 1 newborn with major malformations. In women who suspended RTX/OCR, 37 pregnancies resulted in 3 miscarriages and 33 live births; 1 pregnancy was terminated for malformation. During pregnancy, relapse occurred in 3/42 (7.1%) patients of the NTZ group and 1/33 (3%) of the RTX/OCR group (p = 0.6). After delivery, relapse occurred in 9/42 (21.4%) patients of the NTZ group and 0/33 of the RTX/OCR group (p < 0.01). In the NTZ group, 8/9 relapses occurred in patients who restarted NTZ less than 4 weeks after delivery. The proportion of patients with gadolinium-enhanced and/or new T2 lesions on brain or spinal cord MRI performed after delivery was higher in the NTZ than RTX/OCR group (14/40 [35%] vs 1/31 [3%] patients, p = 0.001), the proportion with EDSS score progression during the period including pregnancy and the year after delivery was higher (7/42 [17%] vs 0/33 patients, p = 0.01), and the proportion fulfilling NEDA-3 during this period was lower (21/40 [53%] vs 30/31 [97%] patients, p < 0.001). DISCUSSION: Suspending RTX/OCR in the year before conception in women with highly active MS was associated with no disease reactivation during and after pregnancy. As previously reported, stopping NTZ at the end of the first trimester was associated with disease reactivation. In women receiving NTZ who are planning pregnancy, a bridge to RTX/OCR for pregnancy or continuing NTZ until week 34 are both reasonable clinical decisions. The RTX/OCR option is more comfortable for women and reduces the exposure of infants to monoclonal antibodies.

Grey-matter sodium concentration as an individual marker of multiple sclerosis severity.

OBJECTIVE: Quantification of brain injury in patients with variable disability despite similar disease duration may be relevant to identify the mechanisms underlying disability in multiple sclerosis (MS). We aimed to compare grey-matter sodium abnormalities (GMSAs), a parameter reflecting neuronal and astrocyte dysfunction, in MS patients with benign multiple sclerosis (BMS) and non-benign multiple sclerosis (NBMS). METHODS: We identified never-treated BMS patients in our local MS database of 1352 patients. A group with NBMS was identified with same disease duration. All participants underwent 23Na magnetic resonance imaging (MRI). The existence of GMSA was detected by statistical analysis. RESULTS: In total, 102 individuals were included (21 BMS, 25 NBMS and 56 controls). GMSA was detected in 10 BMS and 19 NBMS (11/16 relapsing-remitting multiple sclerosis (RRMS) and 8/9 secondary progressive multiple sclerosis (SPMS) patients) (p = 0.05). On logistic regression including the presence or absence of GMSA, thalamic volume, cortical grey-matter volume and T2-weighted lesion load, thalamic volume was independently associated with BMS status (odds ratio (OR) = 0.64 for each unit). Nonetheless, the absence of GMSA was independently associated when excluding patients with significant cognitive alteration (n = 7) from the BMS group (OR = 4.6). CONCLUSION: Detection of GMSA in individuals and thalamic volume are promising to differentiate BMS from NBMS as compared with cortical or whole grey-matter atrophy and T2-weighted lesions.

Pure Relapsing Short Myelitis: Part of the Multiple Sclerosis Spectrum or New Entity?

BACKGROUND AND OBJECTIVES: Pure relapsing short myelitis with clinical and paraclinical features suggesting multiple sclerosis (MS) has been described recently. Here, we evaluated the existence of this potential new form of MS by retrospectively searching for similar cases in the databases of the French tertiary MS centers. METHODS: Patients were included based on the present criteria: at least 2 short (<3 vertebral segments) myelitis episodes; minimum follow-up of 3 years; no MS-like brain lesion during all the follow-up; tested negative for both anti-myelin oligodendrocyte glycoprotein and anti-aquaporin 4 antibodies in serum; presence of oligoclonal bands in CSF; and comprehensive workup to exclude alternative diagnoses. RESULTS: Eighteen patients fulfilled all criteria. The sex ratio (females/males) was 5/1; the median (range) age at first relapse was 35.5 (25-54) years, the disease duration was 80.5 (50-308) months, and the annualized relapse rate was 0.36 (0.1-0.5). The median (range) number of relapses per patient was 2 (2-5), and the median (range) Expanded Disability Status Scale score at last follow-up was 1 (0-7.5). In CSF, the median (range) protein level was 0.34 g/L (0.18-0.77), and the median (range) number of mononuclear cells was 3 (0-28). Spinal cord MRI demonstrated a median (range) number of 2 (1-5) lesions per examination and 3 [1-7] on the last examination. Fifty-five percent of lesions involved the cervical levels. Secondary progressive evolution occurred in 3 of 18 (17%) patients. DISCUSSION: Pure spinal MS could be a rare entity in the MS disease spectrum. However, the existence of a distinct entity in the inflammatory CNS disorders cannot be excluded.

Hypogammaglobulinemia and Infections in Patients With Multiple Sclerosis Treated With Rituximab.

BACKGROUND AND OBJECTIVES: To determine the frequency of hypogammaglobulinemia and infections in patients with multiple sclerosis (PwMS) receiving rituximab (RTX). METHODS: This prospective observational study included all consecutive PwMS receiving RTX at the university hospital of Marseille, France, between 2015 and 2020. Patient visits occurred at least every 6 months. RESULTS: We included 188 patients (151 with relapsing-remitting MS; the mean age was 43.4 years [SD 12.9], median disease duration 10 years [range 0-36], median Expanded Disability Status Scale 5 [range 0-8], median follow-up 3.5 years [range 1-5.8], and median number of RTX infusions 5 [range 1-9]). Overall, 317 symptomatic infections and 13 severe infections occurred in 133 of 188 (70.7%) and 11 of 188 (5.9%) patients, respectively. After 4 years, 24.4% of patients (95% CI 18.0-33.1) were free of any infection and 92.0% (95% CI 87.1-97.1) had not experienced a severe infection. At RTX onset, the immunoglobulin G (IgG) level was abnormal in 32 of 188 (17%) patients. After RTX, IgG level was <7, <6, <4 and <2 g/L for 83 (44%), 44 (23.4%), 8 (4.2%) and 1 (0.53%) patients, respectively. The risk of infection was associated with reduced IgG levels (multivariate Cox proportional hazards hazard ratio [HR] = 0.86, 95% CI 0.75-0.98, p = 0.03). The risk of reduced IgG level <6 g/L increased with age (HR = 1.36, 95% CI 1.05-1.75, p = 0.01). DISCUSSION: In PwMS receiving RTX, reduced IgG level was frequent and interacted with the risk of infection.

Determining the best window for BNT162b2 mRNA vaccination for SARS-CoV-2 in patients with multiple sclerosis receiving anti-CD20 therapy.

We studied the serologic response to the BNT162b2 mRNA vaccine at four weeks after the second dose in patients with RRMS treated with rituximab with extended-interval dosing (n = 26). At four weeks, 73% of patients were seropositive. No patient without B cells at the first dose (n = 4) was seropositive. Four of seven (57%) patients with B-cell proportion >0% and ≤5% were seropositive. All patients with B-cell proportion >5% (n = 15) were seropositive. In all patients, quantitative ELISA measures after vaccination were correlated with B-cell counts measured before vaccination. In patients receiving rituximab, seropositivity after BNT162b2 mRNA vaccination emerged only after B-cell repopulation.

TNF-α inhibitors used as steroid-sparing maintenance monotherapy in parenchymal CNS sarcoidosis.

OBJECTIVE: To assess the efficacy of tumour necrosis factor-α (TNF-α) inhibitors used as steroid-sparing monotherapy in central nervous system (CNS) parenchymal sarcoidosis. METHODS: The French Multiple Sclerosis and Neuroinflammation Centers retrospectively identified patients with definite or probable CNS sarcoidosis treated with TNF-α inhibitors as steroid-sparing monotherapy. Only patients with CNS parenchymal involvement demonstrated by MRI and imaging follow-up were included. The primary outcome was the minimum dose of steroids reached that was not associated with clinical or imaging worsening during a minimum of 3 months after dosing change. RESULTS: Of the identified 38 patients with CNS sarcoidosis treated with TNF-α inhibitors, 23 fulfilled all criteria (13 females). Treatments were infliximab (n=22) or adalimumab (n=1) for a median (IQR) of 24 (17-40) months. At treatment initiation, the mean (SD) age was 41.5 (10.5) years and median (IQR) disease duration 22 (14-49.5) months. Overall, 60% of patients received other immunosuppressive agents before a TNF-α inhibitor. The mean (SD) minimum dose of steroids was 31.5 (33) mg before TNF-α inhibitor initiation and 6.5 (5.5) mg after (p=0.001). In all, 65% of patients achieved steroids dosing <6 mg/day; 61% showed clinical improvement, 30% stability and 9% disease worsening. Imaging revealed improvement in 74% of patients and stability in 26%. CONCLUSION: TNF-α inhibitors can greatly reduce steroids dosing in patients with CNS parenchymal sarcoidosis, even refractory. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that TNF-α inhibitor used as steroid-sparing monotherapy is effective for patients with CNS parenchymal sarcoidosis.

Rituximab-Induced Hypogammaglobulinemia and Infections in AQP4 and MOG Antibody-Associated Diseases.

OBJECTIVE: To determine the potential association between infections and rituximab (RTX)-induced hypogammaglobulinemia among patients with CNS inflammatory diseases. METHODS: We included in a prospective observational study all consecutive adults with aquaporin 4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG) antibody-positive disorders treated with RTX. Dosing schedule was adapted to memory B-cell measurement. RESULTS: We included 48 patients (mean age 47 [SD: 14] years; 77% females; 31 AQP4 positive and 17 MOG positive). The median follow-up was 3.6 years (range: 0.9-8.1 years). The median number of RTX infusions was 8 (range: 2-14). The median dosing interval was 6 months (range: 1.7-13.7 months). Sixty-seven symptomatic infections (SIs) were observed in 26 of 48 (54%) patients, including 13 severe infections in 9 (19%). Urinary and lower respiratory tract infections were the most frequent, representing 42% and 21% of SI. At RTX onset, the immunoglobulin G (IgG) level was abnormal in 3 of 48 (6%) patients. After RTX, 15 (31%), 11 (23%), 3 (6%), and 0 of 48 patients showed sustained IgG level <7, <6, <4, and <2 g/L, respectively. On multivariate Cox proportional hazards analysis, the main variables explaining the risk of SI were the presence of urinary tract dysfunction (hazard ratio [HR] = 34, 95% CI 4-262, p < 0.001), the dosing intervals (HR = 0.98, 95% CI 0.97-0.99, p < 0.001), and the interaction between IgG level and urinary tract dysfunction (HR = 0.67, 95% CI 0.53-0.85, p < 0.005). IgG level <6 g/L during RTX was associated with male sex (HR = 4, 95% CI 1.4-11.4, p < 0.01) and previous immunosuppression (HR = 3.4, 95% CI 1.2-10, p < 0.05). CONCLUSIONS: RTX used as maintenance therapy in CNS inflammatory diseases is frequently associated with reduced IgG level and increases the infection risk of the most vulnerable patients.

Maintenance of natalizumab during the first trimester of pregnancy in active multiple sclerosis.

BACKGROUND: Planning pregnancy in patients with active multiple sclerosis (MS) is highly challenging because treatment withdrawn may be associated with dramatic disease reactivation. OBJECTIVE: To compare two strategies for women with active MS who were planning pregnancy: stopping natalizumab (1) at the end of the first trimester and (2) at conception. METHODS: Standardized strategy for women with active MS was initiated in our department. Maintenance of natalizumab until the end of first trimester was recommended ("secured first trimester" (SFT)). When patients refused, they were advised to continue until conception ("secured conception" (SC)). Predictors of disease activity during pregnancy were assessed. RESULTS: Forty-six pregnancies were prospectively followed (30 with SFT and 16 with SC). One congenital anomaly occurred in the SC group. The proportions of patients with relapse and disability progression during pregnancy were lower in the SFT than in the SC group (3.6% vs 38.5%, p < 0.005 and 3.6% vs 30.8%, p < 0.05, respectively). Predictors of relapse and disability progression during pregnancy were the time when natalizumab was stopped (conception vs end of first trimester) and the number of relapses during the year before natalizumab. CONCLUSION: Maintaining natalizumab during the first trimester may reduce the risk of disease reactivation during pregnancy in patients with active MS.

Comparison of rituximab originator (MabThera®) to biosimilar (Truxima®) in patients with multiple sclerosis.

BACKGROUND: Rituximab's originator MabThera® or Rituxan® has demonstrated high efficacy in multiple sclerosis (MS). Because of the patent expiration, rituximab biosimilars have been developed. However, because a biosimilar is not the exact copy of the originator, the efficacy and safety of a biosimilar may significantly differ. OBJECTIVES: To compare the efficacy and safety of the biosimilar Truxima® and the originator MabThera® in MS. METHODS: Consecutive MS patients receiving MabThera® or Truxima® were prospectively followed during 1 year after treatment introduction. Allocation to each treatment depended on the period of introduction and not the physician's choice. Lymphocyte count, clinical and magnetic resonance imaging (MRI) activity, Expanded Disability Status Scale (EDSS), and adverse events were compared. RESULTS: In total, 105 and 40 patients received MabThera® and Truxima®, respectively. The two groups did not differ in baseline characteristics. Effect on CD19+ lymphocytes and disease activity were similar during follow-up. EDSS remained stable, with no difference between groups. Adverse events were similar between groups. CONCLUSION: The efficacy and safety of the rituximab biosimilar Truxima® seem equivalent to the originator MabThera® in MS patients. Truxima® could represent a relatively cheap and safe therapeutic alternative to MabThera® and could improve access to highly efficient therapy for MS in low- or middle-income countries.

Extending rituximab dosing intervals in patients with MS during the COVID-19 pandemic and beyond?

OBJECTIVE: To evaluate disease activity in patients with relapsing-remitting MS (RRMS) receiving rituximab with an extended dosing interval. METHODS: In the context of COVID-19 pandemic, this was an interim analysis of an ongoing prospective observational study of patients who were stable on rituximab for at least 6 months and who had a planned extended dosing interval of 24 months. Only data for patients with active RRMS before rituximab were analyzed. RESULTS: Among 177 patients receiving rituximab, 33 had RRMS and MRI activity before rituximab and at least 8 months of follow-up after the last infusion. The mean (SD) age was 40 (14) years, 25 were females, the mean disease duration was 10 (6.8) years, the mean annual relapse rate (ARR) before rituximab was 1.7 (1.3), and the median Expanded Disability Status Scale (EDSS) score before rituximab was 4.5 (1-7). Before extended dosing, when rituximab was infused every 6 months, the mean (SD) ARR decreased to 0.04 (0.1) (p < 0.0001) and the EDSS score to 4 (0-7) (p = 0.04). At the time of this analysis, the median follow-up since the last infusion was 11 (8-31) months. No patient showed relapse or disability progression. In total, 30 patients had at least 1 MRI performed since the last infusion (median time between the last MRI and the last infusion 10 [8-31] months). No MRI showed activity. The CD19+ cell proportion was >1% for 10 of 25 patients at the last count (median time 8 [6-25] months). CONCLUSIONS: An extended dosing interval for rituximab for patients with stable MS during the COVID-19 pandemic may be associated with a low risk of disease activity.

Comparison of the Response to Rituximab between Myelin Oligodendrocyte Glycoprotein and Aquaporin-4 Antibody Diseases.

OBJECTIVE: To compare response to rituximab (RTX) between adult patients positive for myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) antibodies. METHODS: We prospectively studied adult patients with MOG or AQP4 antibodies who received RTX under an individualized dosing schedule adapted to the biological effect of RTX monitored by memory B-cell measurement. Memory B cells were counted monthly and when relapse occurred. The biological effect of RTX was considered significant with <0.05% memory B cells in peripheral blood lymphocytes. RESULTS: In 16 patients with MOG antibodies and 29 with AQP4 antibodies, mean follow-up was 19 (range = 9-38) and 38 (13-79) months. Under RTX, 10 relapses occurred in 6 of 16 (37.5%) patients with MOG antibodies, and 13 occurred in 7 of 29 (24%) with AQP4 antibodies. The median time of relapse after the most recent infusion was 2.6 (0.6-5.8) and 7 (0.8-13) months, respectively (p < 0.001). Memory B cells had reemerged in 2 of 10 (20%) relapses in patients with MOG antibodies and 12 of 13 (92.5%) with AQP4 antibodies (p < 0.001). INTERPRETATION: In AQP4 antibody-associated disorder, relapse mostly occurs when the biological effect of RTX decreases, which argues for treatment efficacy. In MOG antibody-associated disorder, the efficacy of RTX is not constant, because one-third of patients showed relapse despite an effective biological effect of RTX. In this subpopulation, memory B-cell depletion was unable to prevent relapse, which was probably caused by different immunological mechanisms. These findings should be used to improve treatment strategies for MOG antibody-associated disorder. ANN NEUROL 2020;87:256-266.

Clinical presentation, treatment and outcome of IgG4-related pachymeningitis: From a national case registry and literature review.

Pachymeningitis is rare, either idiopathic or secondary to inflammatory disorders, after tumoral, surgical or infectious causes have been excluded. The fibroinflammatory IgG4-related disease is one of the etiologies of pachymeningitis with only few cases reported yet. From a single referral regional center, we evaluated the frequency of IgG4-related disease as the cause of inflammatory pachymeningitis in 10% of cases. From a National case registry of IgG4-related disease the pachymeningitis frequency was 4.1%. We report eight new cases with cranial, spinal or both involvements and a literature review of 46 pathological proven cases. We observed that IgG4-related pachymeningitis is in most cases not associated to extra-neurological manifestations of the disease. Only 27% of spinal and 40% of cranial IgG4-related pachymeningitis are associated with other disease localizations. First line treatment strategies included surgery and steroids. The use of immunosuppressants or rituximab was necessary in 18% of spinal and 54% of cranial localizations. Some patients remained with sequellae and clinical and/or radiological improvement can be difficult to obtain.

Efficacy of rituximab in refractory RRMS.

OBJECTIVE: To investigate the efficacy of rituximab as rescue therapy in patients with relapsing-remitting multiple sclerosis (RRMS) and persistent disease activity confirmed by magnetic resonance imaging (MRI) despite immunosuppressive disease-modifying therapy (DMT). METHODS: In this observational nationwide retrospective multicenter study, we first identified 351 off-label rituximab-treated patients through a cohort of 15,984 RRMS patients. In this group, we identified patients with disease activity prior to rituximab confirmed by MRI (one or more new T2 lesion and/or gadolinium-enhancing lesion) despite immunosuppressive DMT (fingolimod, natalizumab, or mitoxantrone) with a follow-up after rituximab initiation longer than 6 months. Outcome data were collected from the French Observatory of Multiple Sclerosis (OFSEP) register and medical charts. RESULTS: A total of 50 patients were identified. Median rituximab treatment duration was 1.1 (0.5-6.4) year. Mean annualized relapse rate significantly decreased from 0.8 during last immunosuppressive DMT to 0.18 after rituximab ( p < 0.0001). While 72% of patients showed gadolinium-enhancing lesions on the last MRI performed during last immunosuppressive DMT, 8% of them showed gadolinium-enhancing lesions on the first MRI performed 6.1 (range 1.4-18.4) months after rituximab ( p < 0.0001). CONCLUSION: This study provides level IV evidence that rituximab reduces clinical and MRI disease activity in patients with active RRMS despite immunosuppressive DMT.