Annualized Relapse Rate Research Articles

Efficacy of Dimethyl Fumarate in Young Adults with Relapsing-Remitting Multiple Sclerosis: Analysis of the DEFINE, CONFIRM, and ENDORSE Studies.

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

Rituximab Use in Aggressive Pediatric Multiple Sclerosis: A Case Report

Pediatric-onset Multiple Sclerosis (POMS) is a chronic inflammatory demyelinating disorder affecting the central nervous system in children. It can lead to debilitating motor and cognitive sequelae. Disease modifying therapies have been used in children as well as adults, with similarities observed in terms of tolerance, and side-effect profiles. At present the consensus in management of Pediatric MS is based mainly upon adult-based treatment trials. Multiple factors are taken into consideration, including disease activity, coexisting morbidities, patient-based preference, and socioeconomic factors. Rituximab, has shown in numerous case series and reports, to be efficient and well tolerated. We report a female child with a relapsing, progressively debilitating CNS demyelinating disease with poor compliance to Disease-Modifying therapies, and breakthrough relapses during Interferon Beta-1b and Fingolimod trials. After rituximab therapy commencement, she had shown reduction in her annualized relapse rate, improvement in her disability scores; and stability in serial neuroimaging during the subsequent 27 months of regular follow-ups.

Therapeutic response to rituximab in seropositive neuromyelitis optica: Experience from a tertiary care center in South India.

Neuromyelitis optica (NMO) is a severe central nervous system demyelinating disease caused by autoantibodies to anti-aquaporin-4 immunoglobulin-G (AQP4-IgG). Rituximab, a monoclonal antibody targeting CD20 cells, is effective in neuromyelitis optica spectrum disorder (NMOSD) in several observational studies and small randomized controlled trials. However, this includes both AQP4-IgG antibody positive and negative cases. Whether rituximab is more effective in seropositive NMO is unknown. The aim of the study was to determine the efficacy of rituximab in seropositive NMO. This single-center ambispective study with retrospective data collection and prospective follow-up included patients with NMOSD who were positive for AQP4-Ig-G and treated with rituximab. Efficacy outcomes assessed were annualized relapse rate (ARR), disability progression by expanded disability status scale (EDSS), very good outcome (defined as no relapse and an EDSS ≤3.5), and persistent antibody positivity. Safety was also monitored. Between June 2017 and December 2019, 15 AQP4-IgG-positive cases were identified. The mean (± SD) age was 36 ± 17.9 years and 73.3% were females. Transverse myelitis followed by optic neuritis was the most common presentations. Rituximab was initiated after a median period of 19-weeks from the disease onset. The mean number of rituximab doses received was 6.4 ± 2.3. After a mean follow-up duration of 107 ± 74.7 weeks from the first dose of rituximab, ARR significantly reduced from 0.5 ± 0.9 to 0.02 ± 0.08, difference 0.48 ± 0.86 (95% confidence intervals [CI], 0.0009-0.96; P = 0.05). The number of relapses also reduced significantly from 0.6 ± 0.8-0.07 ± 0.26 , a difference of 0.53 ± 0.91 (95% CI, 0.026-1.05; P = 0.041). EDSS also significantly reduced from 5.6 ± 2.5-3.3 ± 2.9 , a difference of 2.23 ± 2.36 (95% CI, 0.93-3.54; P = 0.003). Very good outcome was obtained in 73.3% (11 of 15); P = 0.002. AQP4-IgG remained positive in 66.7% (4 of 6) when repeated after a mean period of 149.5 ± 51.1 weeks after the first dose of rituximab. Neither pre-treatment ARR, EDSS, time to initiate rituximab, the total number of rituximab doses, or time to repeat AQP4-IgG were significantly associated with persistent antibody positivity. No serious adverse events were observed. Rituximab exhibited high efficacy and good safety in seropositive NMO. Larger trials in this subgroup are warranted to confirm these findings.

Meta-analysis of the effectiveness of relapse prevention therapy for myelin-oligodendrocyte glycoprotein antibody-associated disease.

Approximately 40% of adults and 30% of children with Myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) experience a relapsing course, but the optimal relapse prevention therapy remains unclear. A meta- analysis was conducted to investigate the efficacy of azathioprine (AZA), mycophenolate mofetil (MMF), rituximab (RTX), maintenance intravenous immunoglobulin (IVIG), and tocilizumab (TCZ) in prevention of attacks in MOGAD. English and Chinese-language articles published from January 2010 to May 2022 were searched in PubMed, Embase, Web of Science, Cochrane, Wanfang Data, China National Knowledge Infrastructure (CNKI), and China Science and Technology Journal Database (CQVIP). Studies with fewer than three cases were excluded. Meta-analysis of the relapse-free rate, the change of annualized relapse rate (ARR)and Expanded Disability Status Scale (EDSS) scores before and after treatment, and an age subgroup analysis was performed. A total of 41 studies were included. Three were prospective cohort studies, one was an ambispective cohort study, and 37 were retrospective cohort studies or case series. Eleven, eighteen, eighteen, eight, and two studies were included in the meta-analysis for relapse-free probability after AZA, MMF, RTX, IVIG, and TCZ therapy, respectively. The proportions of patients without relapse after AZA, MMF, RTX, IVIG, and TCZ were 65% [95% confidence interval (CI):49%-82%]), 73% (95%CI:62%-84%), 66% (95%CI:55%-77%), 79% (95%CI:66%-91%), and 93% (95%CI:54%-100%), respectively. The relapse-free rate did not significantly differ between the children and adults treated with each medication. Six, nine, ten, and three studies were included in the meta-analysis for the change of ARR before and after AZA, MMF, RTX, and IVIG therapy, respectively. ARR was significantly decreased after AZA, MMF, RTX, and IVIG therapy with a mean reduction of 1.58 (95%CI: [-2.29--0.87]), 1.32 (95%CI: [-1.57--1.07]), 1.01 (95%CI: [-1.34--0.67]), and 1.84 (95%CI: [-2.66--1.02]), respectively. The change in ARR did not significantly differ between children and adults. AZA, MMF, RTX, maintenance IVIG, and TCZ all reduce the risk of relapse in both pediatric and adult patients with MOGAD. The literatures included in the meta-analysis were mainly retrospective studies, so large randomized prospective clinical trials are needed to compare the efficacy of different treatments.

Outcomes during and after long-term tocilizumab treatment in patients with giant cell arteritis

ObjectiveTo assess outcomes in giant cell arteritis (GCA) patients during and after long-term tocilizumab (TCZ) treatment.MethodsRetrospective analysis of GCA patients treated with TCZ at a single centre (2010–2022). Time to...

The impact of relapse definition and measures of durability on MS clinical trial outcomes

Background: Definitions of trial measures are consequential to accurately capturing outcomes and cross-trial comparability, particularly for derivative measures. Objective: Using CombiRx, examine the impact of relapse definition on endpoints and evaluate the durability of progression measures in Relapsing Remitting Multiple Sclerosis (RRMS). Methods: CombiRx relapse types were distinguished by the presence or timing of Expanded Disability Status Scale (EDSS) increase. Using the broadest definition of relapse, progression endpoints were assessed in patients without relapses on trial. Durability compared EDSS at study end and time of worsening. Results: Broadening relapse definition to the most inclusive definition increased annualized relapse rate (ARR) threefold in all arms and decreased progression independent of relapse activity (PIRA), defined as 6-month confirmed disability worsening (6M CDW) without relapse, by 44%. Neither PIRA nor PIA (progression independent of any inflammatory activity) guaranteed durable worsening, with 43% and 40%, respectively, improving by end of study. Multivariate analysis showed two CDW events, not relapse, predicted durability among patients meeting 6M CDW. Conclusions: The stringency of relapse definition impacted absolute ARR and composite endpoints in RRMS. Despite the most generous relapse definition, 43% of patients meeting PIRA on trial did not have durable worsening suggesting that relapse definition and durability should be considered to avoid overestimating progression in RRMS trials.

Cost Per Relapse Avoided for Ozanimod Versus Other Selected Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis in the United States.

This study assessed the cost-effectiveness of ozanimod compared with commonly used disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS). Annualized relapse rate (ARR) and safety data were obtained from a network meta-analysis (NMA) of clinical trials of RRMS treatments including ozanimod, fingolimod, dimethyl fumarate, teriflunomide, interferon beta-1a, interferon beta-1b, and glatiramer acetate. ARR-related number needed to treat (NNT) relative to placebo and annual total MS-related healthcare costs was used to estimate the incremental annual cost per relapse avoided with ozanimod vs each DMT. ARR and adverse event (AE) data were combined with drug costs and healthcare costs to manage relapses and AEs in order to estimate annual cost savings with ozanimod vs other DMTs, assuming a 1million USD fixed treatment budget. Treatment with ozanimod was associated with lower incremental annual healthcare costs to avoid a relapse, ranging from $843,684 vs interferon beta-1a (30μg; 95% confidence interval [CI] - $1,431,619, - $255,749) to $72,847 (95%CI - $153,444, $7750) vs fingolimod. Compared with all other DMTs, ozanimod was associated with overall healthcare cost savings ranging from $8257 vs interferon beta-1a (30μg) to $2178 vs fingolimod. Compared with oral DMTs, ozanimod was associated with annual cost savings of $6199 withteriflunomide 7mg, $4737 withteriflunomide 14mg, $2178 withfingolimod, and $2793 withdimethyl fumarate. Treatment with ozanimod was associated with substantial reductions in annual drug costs and total MS-related healthcare costs to avoid relapses compared with other DMTs. In the fixed-budget analysis, ozanimod demonstrated a favorable cost-effective profile relative to other DMTs.

Long-Term Effectiveness and Safety of Natalizumab in African American and Hispanic/Latino Patients with Early Relapsing-Remitting Multiple Sclerosis: STRIVE Data Analysis.

In STRIVE, natalizumab treatment demonstrated effectiveness in clinical, magnetic resonance imaging (MRI), and patient-reported outcomes (PROs) in patients with early relapsing-remitting multiple sclerosis (RRMS). This post hoc analysis examined the effectiveness and safety of natalizumab in patients who self-identified as either Black/African American (AA) or Hispanic/Latino. Clinical, MRI, and PROs were assessed for the Black/AA subgroup (n = 40) and compared with the non-Hispanic White subgroup (n = 158). As a result of the very small sample size, outcomes for the Hispanic/Latino subgroup (n = 18) were assessed separately, including a sensitivity analysis with Hispanic/Latino patients who completed the 4-year study on natalizumab. Clinical, MRI, and PROs were comparable between the Black/AA and non-Hispanic White subgroups except for MRI outcomes at year1. A higher proportion of non-Hispanic White than Black/AA patients achieved MRI no evidence of disease activity (NEDA; 75.4% vs. 50.0%, p = 0.0121) and no new or newly enlarging T2 lesions (77.6% vs. 50.0%, p = 0.0031) at year1; these differences were not observed in years2-4 of the study. For the Hispanic/Latino subgroup in the intent-to-treat population, 46.2% and 55.6% achieved NEDA at years1 and 2; 66.7% and 90.0% achieved clinical NEDA at years3 and 4. Annualized relapse rate was reduced by 93.0% at year1 versus the year before natalizumab initiation; this reduction was maintained throughout the study. Over 4years, 37.5-50.0% of patients had a clinically meaningful improvement in their Symbol Digit Modalities Test score, and 81.8-100.0% and 90.9-100.0% had stable/improved Multiple Sclerosis Impact Scale-29 physical and psychological scores, respectively. Similar results were observed in the sensitivity analysis with Hispanic/Latino subgroup of the 4-year natalizumab completers. These results highlight the effectiveness and safety of natalizumab in patients with early RRMS who self-identified as Black/AA or Hispanic/Latino. GOV: NCT01485003.

Results of treatment with alemtuzumab in a Spanish cohort of patients with multiple sclerosis in the real world: The RealMS study.

Alemtuzumab (ALZ) is a humanized monoclonal antibody approved for the treatment of patients with highly active relapsing-remitting multiple sclerosis (RRMS) administered in two annual courses. The objective of this study was to describe the effectiveness and safety data of ALZ and to report the health resource utilization in patients receiving this treatment. In this retrospective, non-interventional study, information was retrieved from patients' medical charts at one center in Spain. Included patients were ≥18 years old, and ALZ treatment was initiated between 1 March 2015 and 31 March 2019, according to routine clinical practice and local labeling. Of 123 patients, 78% were women. The mean (standard deviation, SD) age of patients at diagnosis was 40.3 (9.1) years, and the mean time since diagnosis was 13.8 (7.3) years. Patients were previously treated with a median (interquartile range; IQR) number of two (2.0-3.0) disease-modifying treatments (DMTs). Patients were treated with ALZ for a mean (SD) of 29.7 (13.8) months. ALZ reduced the annualized relapse rate (ARR) (1.5 before vs. 0.05 after; p < 0.001) and improved the median EDSS (4.63 before vs. 4.00 after; p < 0.001). Most (90.2%) patients were relapse-free while receiving ALZ. The mean number of gadolinium-enhancing [Gd+] T1 lesions was reduced (1.7 before vs. 0.1 after; p < 0.001), and the mean number of T2 hyperintense lesions was maintained (35.7 before vs. 35.4 after; p = 0.392). A total of 27 (21.9%) patients reported 29 autoimmune diseases: hyperthyroidism (12), hypothyroidism (11), idiopathic thrombocytopenic purpura (ITP) (3), alopecia areata (1), chronic urticaria (1), and vitiligo (1). The mean number of health resources (outpatient visits, emergency room visits, hospital admissions, and tests performed in the hospital) used while patients were treated with ALZ progressively decreased from year 1 to year 4, except for a slight increase at year 2 of outpatient visits. The ReaLMS study provides real-world evidence that ALZ can promote clinical and magnetic resonance imaging disease remission, as well as disability improvement in patients with MS, despite several prior DMT failures. The ALZ safety profile was consistent with data available from clinical trials and other real-world studies. Healthcare resource use was reduced throughout the treatment period.

Treatment of multiple sclerosis with rituximab: A Spanish multicenter experience.

Rituximab (RTX) is considered a potential therapeutic option for relapsing-remitting (RRMS) and progressive forms (PMS) of multiple sclerosis (MS). The main objective of this work was to investigate the effectiveness and safety of rituximab in MS. Observational multicenter study of clinical and radiological effectiveness and safety of rituximab in RRMS and PMS. A total of 479 rituximab-treated patients were included in 12 Spanish centers, 188 RRMS (39.3%) and 291 (60.7%) PMS. Despite standard treatment, the annualized relapse rate (ARR) the year before RTX was 0.63 (SD: 0.8) and 156 patients (41%) had at least one gadolinium-enhanced lesion (GEL) on baseline MRI. Mean EDSS had increased from 4.3 (SD: 1.9) to 4.8 (SD: 1.7) and almost half of the patients (41%) had worsened at least one point. After a median follow-up of 14.2 months (IQR: 6.5-27.2), ARR decreased by 85.7% (p < 0.001) and GEL by 82.9%, from 0.41 to 0.07 (p < 0.001). A significant decrease in EDSS to 4.7 (p = 0.046) was observed after 1 year of treatment and this variable remained stable during the second year of therapy. There was no evidence of disease activity in 68% of patients. Infusion-related symptoms were the most frequent side effect (19.6%) and most were mild. Relevant infections were reported only in 18 patients (including one case of probable progressive multifocal leukoencephalopathy). Rituximab could be an effective and safe treatment in RRMS, including aggressive forms of the disease. Some selected PMS patients could also benefit from this treatment.

Effects of horizontal versus vertical switching of disease-modifying treatment after platform drugs on disease activity in patients with relapsing–remitting multiple sclerosis in Austria

ObjectivesTo compare in a nationwide observational cohort the effectiveness, frequency and reasons for treatment interruption of dimethylfumarate (DMF) and teriflunomide (TERI) (horizontal switchers) versus alemtuzumab (AZM), cladribine (CLAD), fingolimod (FTY), natalizumab (NTZ), ocrelizumab (OCR) and ozanimod (OZA) (vertical switchers) in patients with relapsing–remitting multiple sclerosis (pwRRMS) and prior interferon beta (IFN-beta) or glatiramer-acetate (GLAT) treatment.Materials and methodsThe “horizontal switch cohort” included 669 and the “vertical switch cohort” 800 RRMS patients. We used propensity scores for inverse probability weighting in generalized linear (GLM) and Cox proportional hazards models to correct for bias in this non-randomized registry study.ResultsEstimated mean annualized relapse rates (ARR) were 0.39 for horizontal and 0.17 for vertical switchers. The incidence rate ratio (IRR) in the GLM model showed an increased relapse probability of 86% for horizontal versus vertical switchers (IRR = 1.86; 95% CI 1.38–2.50; p < 0.001). Analyzing the time to the first relapse after treatment switch by Cox regression, a hazard ratio of 1.58 (95% CI 1.24–2.02; p < 0.001) indicated an increased risk of 58% for horizontal switchers. The hazard ratios for treatment interruption comparing horizontal versus vertical switchers were 1.78 (95% CI 1.46–2.18; p < 0.001).ConclusionsHorizontal switching after a platform therapy resulted in a higher relapse and interrupt probability and was associated with a trend towards less EDSS improvement comparing to vertical switching in Austrian RRMS patients.

Ocrelizumab in pediatric multiple sclerosis.

Ocrelizumab is a recombinant humanized anti-CD20 monoclonal IgG1, approved by FDA and EMA for adult patients with multiple sclerosis (MS). The data on the efficacy and safety of Ocrelizumab for pediatric MS cases are limited. Here, we describe pediatric relapsing-remitting MS (P-RRMS) cases who were treated with Ocrelizumab as a disease-modifying drug. P-RRMS cases who were started Ocrelizumab below 18 years-of-age and followed-up >12 months with Ocrelizumab treatment were included. The primary end-points were annualized relapse rate (ARR) and magnetic resonance imaging (MRI) activity (new/enlarging T2 lesions and new gadolinium (Gd) enhancing lesions). The secondary end-points were the percentage of patients who remain relapse-free and/or free from Gd enhancing lesions, Expanded Disability Status Scale (EDSS) score, and the safety profile of Ocrelizumab. Of 18P-RRMS cases receiving Ocrelizumab, 10 patients fulfilled the inclusion criteria for our study. The median duration of follow-up under Ocrelizumab was 28,3 months (min: 15 months, max: 46 months). Mean ARR decreased from 2.01 (±0.71) to 0 during the follow-up of Ocrelizumab treatment (P<0.0001). None of the patients had MRI activity during the treatment. Mean EDSS decreased from 1.75 (±1.09) to 1.20 (±0.63) from the initiation of Ocrelizumab to the last follow-up of the patients (P=0.024). None of the patients had serious side effects, except one patient who experienced anaphylaxis. Ocrelizumab can be considered a safe and effective treatment option in highly active P-RRMS.

Comparative efficacy and safety of ozanimod and ponesimod for relapsing multiple sclerosis: A matching-adjusted indirect comparison.

Ozanimod and ponesimod are sphingosine 1-phosphate receptor modulators approved by the U.S. Food and Drug Administration for treatment of relapsing forms of multiple sclerosis (MS). Given that no head-to-head trials have assessed these two treatments, we performed a matching-adjusted indirect comparison (MAIC) to compare efficacy and safety outcomes between ozanimod and ponesimod for MS. A MAIC compared efficacy and safety of ozanimod and ponesimod at 2 years. Outcomes included annualized relapse rate (ARR) and percentage change from baseline in brain volume loss (BVL) as well as rates of any treatment-emergent adverse events (TEAEs), serious adverse events (AEs), AEs leading to discontinuation, and other safety outcomes. Individual patient-level data were obtained for ozanimod from the RADIANCE-B trial, while aggregate-level patient data were obtained for ponesimod from the OPTIMUM trial. The MAIC was not anchored owing to lack of a common comparator across the two trials. The following characteristics were matched between the trials' populations: age, sex, time since MS symptom onset, relapses in prior year, Expanded Disability Status Scale score, disease-modifying therapies received in the prior 2 years, absence of gadolinium-enhancing T1 lesions, and percentage of patients from Eastern Europe. After matching, key baseline characteristics were balanced between patients receiving ozanimod and ponesimod. Compared with ponesimod, ozanimod had a numerically lower ARR (rate ratio: 0.80 [95% CI: 0.57, 1.10]) and was associated with a significant reduction in BVL (% change difference: 0.20 [95% CI: 0.05, 0.36]). Additionally, ozanimod was associated with a significantly lower risk of TEAEs (risk difference: -11.9% [95% CI: -16.8%, -7.0%]), AEs leading to discontinuation (-6.1% [95% CI: -8.9%, -3.4%]), and lymphocyte count <0.2K/μL (-2.3% [95% CI: -4.2%, -0.5%]). There were no statistically significant differences in the other safety outcomes. The MAIC results suggest that, compared with ponesimod, ozanimod is more effective in preserving brain volume, is comparable in terms of reducing relapse rates, and has a favorable safety profile.

COVID-19 and its implications on the clinico-radiological course of multiple sclerosis: A case–control study

BackgroundMultiple sclerosis (MS) is an immune-mediated disease that has been related to several risk factors such as various viral infections. We carried out this study in order to establish a relationship between COVID-19 infection and MS severity. MethodsIn a case–control study, we recruited patients with relapsing–remitting multiple sclerosis (RRMS). Patients were divided into two groups based on positive COVID-19 PCR at the end of the enrollment phase. Each patient was prospectively followed for 12 months. Demographical, clinical, and past medical history were collected during routine clinical practice. Assessments were performed every six months; MRI was performed at enrollment and 12 months later. ResultsThree hundred and sixty-two patients participated in this study. MS patients with COVID-19 infection had significantly higher increases in the number of MRI lesions (p: 0.019, OR(CI): 6.37(1.54–26.34)) and EDSS scores (p: 0.017), but no difference was found in total annual relapses or relapse rates. COVID-19 infections were positively correlated with EDSS progression (p: 0.02) and the number of new MRI lesions (p: 0.004) and predicted the likelihood of the number of new MRI lesions by an odds of 5.92 (p: 0.018). ConclusionCOVID-19 may lead to higher disability scores in the RRMS population and is associated with developing new Gd-enhancing lesions in MRI imaging. However, no difference was observed between the groups regarding the number of relapses during follow-up.

Pathophysiology of myelin oligodendrocyte glycoprotein antibody disease.

Myelin Oligodendrocyte Glycoprotein Antibody Disease (MOGAD) is a spectrum of diseases, including optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, and cerebral cortical encephalitis. In addition to distinct clinical, radiological, and immunological features, the infectious prodrome is more commonly reported in MOGAD (37-70%) than NMOSD (15-35%). Interestingly, pediatric MOGAD is not more aggressive than adult-onset MOGAD, unlike in multiple sclerosis (MS), where annualized relapse rates are three times higher in pediatric-onset MS. MOGAD pathophysiology is driven by acute attacks during which T cells and MOG antibodies cross blood brain barrier (BBB). MOGAD lesions show a perivenous confluent pattern around the small veins, lacking the radiological central vein sign. Initial activation of T cells in the periphery is followed by reactivation in the subarachnoid/perivascular spaces by MOG-laden antigen-presenting cells and inflammatory CSF milieu, which enables T cells to infiltrate CNS parenchyma. CD4+ T cells, unlike CD8+ T cells in MS, are the dominant T cell type found in lesion histology. Granulocytes, macrophages/microglia, and activated complement are also found in the lesions, which could contribute to demyelination during acute relapses. MOG antibodies potentially contribute to pathology by opsonizing MOG, complement activation, and antibody-dependent cellular cytotoxicity. Stimulation of peripheral MOG-specific B cells through TLR stimulation or T follicular helper cells might help differentiate MOG antibody-producing plasma cells in the peripheral blood. Neuroinflammatory biomarkers (such as MBP, sNFL, GFAP, Tau) in MOGAD support that most axonal damage happens in the initial attack, whereas relapses are associated with increased myelin damage.

A decade of fingolimod in multiple sclerosis: Insights from a large real-world cohort study

Background and objectivesTen years after its authorization, data about fingolimod use in real-world setting is still scarce. Here we describe the long-term evolution of fingolimod-treated relapsing-remitting MS (RRMS) patients and determine baseline characteristics associated with risk of relapses or disability. MethodsWe analyzed baseline characteristics and clinical evolution of 1227 patients with RRMS treated with fingolimod from 2010 to 2019 in 4 French MS referral centers. We used Cox models to determine risks factors of relapses and sustained EDSS worsening. ResultsMedian follow-up duration was 50 months, and 63% of patients remained fingolimod-treated at the end of follow-up. Mean 5-years annualized relapse rate (ARR) decreased from 0.63 (0.60–0.67) to 0.26 (0.24–0.29, P<0.001), while the mean EDSS rose from 2.5 (2.4–2.6) to 3.0 (2.8–3.1, P<0.001). Female sex, lower age, higher EDSS and use of natalizumab were associated with relapse risk. Female sex was associated with sustained EDSS increase risk. ConclusionsBased on a large real-world cohort, our results confirm the durable reduction of the ARR described in pivot studies. Switching from moderate-efficacy DMT to fingolimod decreased the relapse risk. Switching patients from high-efficacy DMT increased risk of relapse, but the overall five-years ARR remained stable.

SAkuraBONSAI: Protocol design of a novel, prospective study to explore clinical, imaging, and biomarker outcomes in patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorder receiving open-label satralizumab.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare, autoimmune disease of the central nervous system that produces acute, unpredictable relapses causing cumulative neurological disability. Satralizumab, a humanized, monoclonal recycling antibody that targets the interleukin-6 receptor, reduced NMOSD relapse risk vs. placebo in two Phase 3 trials: SAkuraSky (satralizumab ± immunosuppressive therapy; NCT02028884) and SAkuraStar (satralizumab monotherapy; NCT02073279). Satralizumab is approved to treat aquaporin-4 IgG-seropositive (AQP4-IgG+) NMOSD. SAkuraBONSAI (NCT05269667) will explore fluid and imaging biomarkers to better understand the mechanism of action of satralizumab and the neuronal and immunological changes following treatment in AQP4-IgG+ NMOSD. SAkuraBONSAI will evaluate clinical disease activity measures, patient-reported outcomes (PROs), pharmacokinetics, and safety of satralizumab in AQP4-IgG+ NMOSD. Correlations between imaging markers (magnetic resonance imaging [MRI] and optical coherence tomography [OCT]) and blood and cerebrospinal fluid (CSF) biomarkers will be investigated. SAkuraBONSAI is a prospective, open-label, multicenter, international, Phase 4 study that will enroll approximately 100 adults (18-74 years) with AQP4-IgG+ NMOSD. This study includes two patient cohorts: newly diagnosed, treatment-naïve patients (Cohort 1; n = 60); and inadequate responders to recent (<6 months) rituximab infusion (Cohort 2; n = 40). Satralizumab monotherapy (120 mg) will be administered subcutaneously at Weeks 0, 2, 4, and Q4W thereafter for a total of 92 weeks. Disease activity related to relapses (proportion relapse-free, annualized relapse rate, time to relapse, and relapse severity), disability progression (Expanded Disability Status Scale), cognition (Symbol Digit Modalities Test), and ophthalmological changes (visual acuity; National Eye Institute Visual Function Questionnaire-25) will all be assessed. Peri-papillary retinal nerve fiber layer and ganglion cell complex thickness will be monitored using advanced OCT (retinal nerve fiber layer and ganglion cell plus inner plexiform layer thickness). Lesion activity and atrophy will be monitored by MRI. Pharmacokinetics, PROs, and blood and CSF mechanistic biomarkers will be assessed regularly. Safety outcomes include the incidence and severity of adverse events. SAkuraBONSAI will incorporate comprehensive imaging, fluid biomarker, and clinical assessments in patients with AQP4-IgG+ NMOSD. SAkuraBONSAI will provide new insights into the mechanism of action of satralizumab in NMOSD, while offering the opportunity to identify clinically relevant neurological, immunological, and imaging markers.

Association of Higher Ocrelizumab Exposure With Reduced Disability Progression in Multiple Sclerosis.

Ocrelizumab improved clinical and MRI measures of disease activity and progression in three phase 3 multiple sclerosis (MS) studies. Post hoc analyses demonstrated a correlation between the ocrelizumab serum concentration and the degree of blood B-cell depletion, and body weight was identified as the most influential covariate on ocrelizumab pharmacokinetics. The magnitude of ocrelizumab treatment benefit on disability progression was greater in lighter vs heavier patients. These observations suggest that higher ocrelizumab serum levels provide more complete B-cell depletion and a greater delay in disability progression. The current post hoc analyses assessed population exposure-efficacy/safety relationships of ocrelizumab in patients with relapsing and primary progressive MS. Patients in OPERA I/II and ORATORIO were grouped in exposure quartiles based on their observed individual serum ocrelizumab level over the treatment period. Exposure-response relationships were analyzed for clinical efficacy (24-week confirmed disability progression (CDP), annualized relapse rate [ARR], and MRI outcomes) and adverse events. Ocrelizumab reduced new MRI lesion counts to nearly undetectable levels in patients with relapsing or primary progressive MS across all exposure subgroups, and reduced ARR in patients with relapsing MS to very low levels (0.13-0.18). A consistent trend of higher ocrelizumab exposure leading to lower rates of CDP was seen (0%-25% [lowest] to 75%-100% [highest] quartile hazard ratios and 95% confidence intervals; relapsing MS: 0.70 [0.41-1.19], 0.85 [0.52-1.39], 0.47 [0.25-0.87], and 0.34 [0.17-0.70] vs interferon β-1a; primary progressive MS: 0.88 [0.59-1.30], 0.86 [0.60-1.25], 0.77 [0.52-1.14], and 0.55 [0.36-0.83] vs placebo). Infusion-related reactions, serious adverse events, and serious infections were similar across exposure subgroups. The almost complete reduction of ARR and MRI activity already evident in the lowest quartile, and across all ocrelizumab-exposure groups, suggests a ceiling effect. A consistent trend of higher ocrelizumab exposure leading to greater reduction in risk of CDP was observed, particularly in the relapsing MS trials, and was not associated with a higher rate of adverse events. Higher ocrelizumab exposure may provide improved control of disability progression by reducing disease activity below that detectable by ARR and MRI, and/or by attenuating other B-cell-related pathologies responsible for tissue damage. This analysis provides Class III evidence that higher ocrelizumab serum levels are related to greater reduction in risk of disability progression in patients with multiple sclerosis. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in the open-label extension. ClinicalTrials.gov Identifier: NCT01247324 (OPERA I), NCT01412333 (OPERA II), and NCT01194570 (ORATORIO).

Real-World Effectiveness of Natalizumab Extended Interval Dosing in a French Cohort.

Natalizumab, a therapy for relapsing-remitting multiple sclerosis (RRMS), is associated with a risk of progressive multifocal leukoencephalopathy (PML). Over the last several years, practitioners have used off-label extended interval dosing (EID) of natalizumab to reduce PML risk, despite the absence of a large-scale efficacy evaluation. We conducted a retrospective, multicenter cohort study among adults with RRMS receiving stable standard interval dosing (SID), defined as a ≥ 12-month consecutive period of ≥ 11 natalizumab infusions/year in France. We compared the 12-month risk difference of remaining relapse-free (primary endpoint) between patients who switched to EID (≤ 9 natalizumab infusions) and those who remained on SID, with a noninferiority margin of - 11%. We used propensity score methods such as inverse probability treatment weighting (IPTW) and 1:1 propensity score matching (PSM). Secondary endpoints were annualized relapse rate, disease progression, and safety. Baseline characteristics were similar between patients receiving EID (n = 147) and SID (n = 156). The proportion of relapse-free patients 12months postbaseline was 142/147 in the EID (96.6%) and 144/156 in the SID group (92.3%); risk difference (95% CI) 4.3% (- 1.3 to 9.8%); p < 0.001 for non-inferiority. There were no significant differences between relapse rates (0.043 vs. 0.083 per year, respectively; p = 0.14) or Expanded Disability Status Scale mean scores (2.43 vs. 2.72, respectively; p = 0.18); anti-JC virus index values were similar (p = 0.23); and no instances of PML were reported. The comparisons using IPTW (n = 306) and PSM (n = 204) were consistent. These results support the pertinence of using an EID strategy for RRMS patients treated with natalizumab. gov identifier (NCT04580381).

Correlation of brain segmental volume changes with clinical parameters: a longitudinal study in multiple sclerosis patients

To measure the cranial volume differences from 15 different parts in the follow-up of relapsing-remitting multiple sclerosis (RRMS) patients and correlate them with clinical parameters. Forty-seven patients with RRMS were included in the study. Patients were grouped into two categories; low Expanded Disability Status Scale (EDSS) (< 3; group 1), and moderate-high EDSS (≥ 3; group 2). Patients were evaluated with Beck Depression Inventory (BDI), Montreal Cognitive Assessment (MOCA), Symbol Digit Modalities Test (SDMT), Fatigue Severity Scale (FSS), and calculated Annualized Relapse Rate (ARR) scores. Magnetic resonance imaging (MRI) was performed with a 1.5T MRI device (Magnetom AERA, Siemens, Erlangen, Germany) twice in a 1-year period. Volumetric analysis was performed by a free, automated, online MRI brain volumetry software. The differences in volumetric values between the two MRI scans were calculated and correlated with the demographic and clinical parameters of the patients. The number of attacks, disease duration, BDI, and FSS scores were higher in group 2; SDMT was higher in group 1. As expected, volumetric analyses have shown volume loss in total cerebral white matter in follow-up patients (p < 0.001). In addition, putaminal volume loss was related to a higher number of attacks. Besides, a negative relation between FSS with total amygdala volumes, a link between atrophy of globus pallidus and ARR, and BDI scores was found with the aid of network analysis. Apart from a visual demonstration of volume loss, cranial MRI with volumetric analysis has a great potential for revealing covert links between segmental volume changes and clinical parameters.