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Background: Patients with multiple sclerosis (PwMS) have an increased risk of infections. Objectives: To characterize incidence, clinical characteristics, outcomes and risk factors of infections, and serious infections (SIs) in ocrelizumab (OCR)-treated PwMS. Design: Post-hoc analysis of pooled data from 6155 patients in 13 clinical trials. Methods: Descriptive analyses of clinical characteristics and outcomes were reported over ⩽14 years. A Poisson Generalized Estimating Equation model was constructed to examine risk factors in a subgroup of patients with longer exposure to OCR ( n = 2092). Results: Over a median (max) treatment period of 3.7 (13.9) years, 420/6155 patients (6.8%) experienced 583 SIs, excluding coronavirus disease 2019. Incidence rates in relapsing multiple sclerosis (RMS; 1.50 per 100 patient years [95% confidence interval (CI): 1.34–1.68]) and progressive multiple sclerosis (PMS; 3.70 [95% CI: 3.27–4.17]) remained stable over this period. Lower respiratory tract, urinary tract, abdominal and gastrointestinal, and skin infections were the most commonly reported SIs. Most SIs (~90%) resolved, and treatment with OCR was continued in >80% of cases. The presence of 1 or ⩾2 comorbidities (rate ratio = 1.66, 2.73, respectively), recent relapse activity (2.06), and Expanded Disability Status Scale (EDSS) score ⩾6.0 (2.02) were significant risk factors for SIs in patients with RMS treated over a median (max) period of 8.3 (11.2) years. In patients with primary PMS treated over a median (max) period of 7.1 (11.8) years, an EDSS score ⩾6.0 was associated with the greatest risk of SIs, a 4-fold increase (rate ratio, 4.31), followed by abnormal immunoglobulin (Ig)M levels (1.89), the presence of ⩾2 comorbidities (1.80), and having overweight/obesity (1.46). Time on OCR and abnormal IgG levels were not significantly associated with an increased SI risk. Conclusion: Continuous long-term treatment with OCR is associated with a manageable infection risk profile. Optimal disease control and addressing modifiable risk factors may reduce the risk of infections.

Background: In REFLEX, subcutaneous interferon beta-1a (sc IFN β-1a) delayed the onset of multiple sclerosis (MS) in patients with a first clinical demyelinating event (FCDE). Objectives: This post hoc analysis aimed to determine whether baseline serum neurofilament light (sNfL) chain can predict conversion to MS and whether correlations exist between baseline sNfL and magnetic resonance imaging (MRI) metrics. Methods: sNfL was measured for 494 patients who received sc IFN β-1a 44 μg once weekly (qw; n = 168), three times weekly (tiw; n = 161), or placebo ( n = 165) over 24 months. Median baseline sNfL (26.1 pg/mL) was used to define high/low sNfL subgroups. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox’s proportional hazard model to determine factors influencing the risk of conversion to MS. Kaplan–Meier estimates calculated median time-to-conversion to MS (McDonald 2005 criteria) or clinically definite MS (CDMS; Poser criteria). Correlations between sNfL and MRI findings were assessed using Spearman’s rank correlation coefficient ( r ). Results: Multivariable models indicated that high baseline sNfL was associated with the likelihood of converting to MS and inversely to time-to-conversion (HR = 1.3, 95% CI: 1.03–1.64; p = 0.024). Significant additional factors affecting conversion to McDonald MS were on-study treatment (sc IFN β-1a/placebo; qw: HR = 0.59, 95% CI: 0.46–0.76; tiw: HR = 0.45, 95% CI: 0.34–0.59), classification of FCDE (monofocal/multifocal; HR = 0.69, 95% CI: 0.55–0.85), and most baseline imaging findings (T2 and T1 gadolinium-enhancing [Gd+] lesions; HR = 1.02, 95% CI: 1.01–1.03 and HR = 1.07, 95% CI: 1.03–1.11); all p ⩽ 0.001. Conversion to CDMS showed similar results. At month 24, sNfL was strongly correlated with a mean number of combined unique active ( r = 0.71), new T2 ( r = 0.72), and new T1 Gd+ ( r = 0.60) lesions; weak correlations were observed between sNfL and clinical outcomes for all treatment groups. Conclusion: Higher baseline sNfL was associated with an increased risk of MS conversion, a risk that was mitigated by treatment with sc IFN β-1a tiw. Trial registration: ClinicalTrials.gov identifier: NCT00404352. Date registered: 28 November 2006.

Background: Clinical and radiological signs of recurring disease activity (RDA) have been described in patients with multiple sclerosis (pwMS) after discontinuation of fingolimod (FGL). Objective: To describe frequency, severity and potential risk factors for RDA after FGL discontinuation in a large real-world cohort of pwMS. Methods: Post-FGL RDA was defined as evidence of clinical and/or radiological activity within 6 months after FGL discontinuation. Relapses with Expanded Disability Status Scale increase ⩾2 points and/or magnetic resonance imaging (MRI) activity with at least five cerebral gadolinium-enhancing lesions and/or ⩾6 cerebral new T2 lesions were defined as severe recurring disease activity (sRDA). Using a multivariate logistic model, we explored the influence of age, disease duration, sex, clinical, and MRI activity under FGL on the occurrence of RDA. Results: We identified 110 pwMS who discontinued FGL. Thirty-seven (33.6%) developed post-FGL RDA and 13 (11.8%) also fulfilled criteria for sRDA. Younger age at diagnosis [odds ratio (OR) = 1.10, p

Background: Natalizumab is a highly effective monoclonal antibody for the treatment of multiple sclerosis (MS), which can diffuse in different anatomical compartments, including cerebrospinal fluid (CSF) and milk. Objectives: Starting from incidental detection of natalizumab in the CSF of MS patients, the objective of this study was to develope a flow-cytometry-based assay and apply it to quantify natalizumab in body fluids, including milk collected from nursing patients over 180 days and in patients with neutralizing antibodies against natalizumab. Methods: CSF, milk and sera samples from patients with multiple sclerosis were tested by flow-cytometry for binding to a VLA-4 expressing cell line or to a control cell line. A standard curve was prepared by incubating the same cells with natalizumab at 50 μg/ml and serially diluted to 0.005 ng/ml. Binding specificity was confirmed using an anti-natalizumab neutralizing antibody. Results: Our assay was sensitive enough to detect natalizumab in CSF, with a lower detection limit of 1.5 ng/ml. Neutralizing antibodies against natalizumab inhibited binding to the cell line. In breastmilk, the peak concentration was observed during the first 2 weeks after infusion and the average concentration over the observation time was 173.3 ng/ml, with a trend toward increased average milk concentration over subsequent administrations. Conclusion: Routine use of such an assay would enable a better understanding of the safety of therapeutic antibody administration during pregnancy and lactation.

Background: Extended interval dosing of natalizumab is associated with significantly lower progressive multifocal leukoencephalopathy risk compared with every-4-week (Q4W) dosing in patients with relapsing-remitting multiple sclerosis. Previous studies have suggested that natalizumab effectiveness is maintained in patients who switch from Q4W to extended interval dosing but have been limited by a lack of well-matched patient cohorts. Methods: Tysabri Observational Program (TOP) data as of November 2019 were used to identify patients with relapsing-remitting multiple sclerosis treated with natalizumab Q4W and those with a single physician-indicated dosing change from Q4W to every-6-week (Q6W) dosing after ⩾1 year of Q4W treatment. Patients were propensity score matched at the time of the switch from Q4W to Q6W dosing. Clinical outcomes (annualized relapse rate and probability of remaining relapse free or free of 24-week confirmed disability worsening) and safety outcomes were assessed for the two cohorts. Results: This study included 219 pairs of propensity score–matched Q6W and Q4W patients. Annualized relapse rates were similar for Q6W (0.150) and Q4W (0.157) patients. The probability of remaining relapse free [hazard ratio = 1.243 (95% confidence interval = 0.819–1.888); p = 0.307] and of remaining free of 24-week confirmed disability worsening [hazard ratio = 0.786 (95% confidence interval = 0.284–2.176); p = 0.644] did not differ significantly between Q6W and Q4W patients. Summarized safety results for the matched Q6W and Q4W patients are also presented. Conclusion: These real-world findings in well-matched patient cohorts from TOP demonstrate that natalizumab effectiveness is maintained in patients who switch to Q6W dosing after ⩾1 year of Q4W dosing. ClinicalTrials.gov identifier: NCT00493298

Background: EXTEND (NCT01797965), an open-label extension study, evaluated the safety and efficacy of daclizumab beta in participants with relapsing multiple sclerosis (MS) who had completed the randomized DECIDE study. Methods: Eligible participants who received either daclizumab beta or interferon beta-1a in DECIDE received daclizumab beta 150 mg subcutaneously every 4 weeks for up to 5 years in EXTEND, followed by 24 weeks of post-dosing follow-up. Safety and tolerability were evaluated, as were clinical efficacy and magnetic resonance imaging (MRI). EXTEND was terminated ahead of schedule by the sponsors. Results: The total safety population ( N = 1203) received at least one dose of daclizumab beta in EXTEND. In the DECIDE and EXTEND combined periods, the median number of doses of daclizumab beta was 53; median time on treatment was 196 weeks. By 24 September 2018, the end of the study, 110/1203 (9%) participants had completed the protocol-specified treatment period and 1101/1203 (92%) had experienced an adverse event (AE). The most commonly reported AEs were MS relapse, nasopharyngitis, and upper respiratory tract infection. Hepatic events (18%), cutaneous events (45%), and infections (62%) were common treatment-related AEs. The incidence of serious AEs was 29%, most commonly MS relapse and infections. The incidence of immune-mediated disorders was 2%; three of seven were encephalitis. Two of six deaths were considered treatment related. In participants who received continuous daclizumab beta throughout DECIDE and EXTEND, the treatment effects on clinical and MRI outcomes were maintained for up to 6 years. Conclusion: Results from the combined DECIDE-EXTEND study elucidate outcomes of longer-term treatment with daclizumab beta in the clinical trial setting and underscore the importance of pharmacovigilance with immunomodulatory therapies in the real-world setting.

Introduction: We report safety and efficacy in patients treated with dimethyl fumarate (DMF) for ~9 years in ENDORSE. Lymphocyte analysis data are also reported. Methods: Incidence of serious adverse events (SAEs), discontinuations due to adverse events (AEs), annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg twice daily (BID): placebo (PBO)/DMF (PBO for years 0–2 /DMF for years 3–9) or continuous (DMF/DMF) treatment; newly diagnosed patients were included. Annual magnetic resonance imaging (MRI) was evaluated in patients from the MRI cohort of DEFINE/CONFIRM. For the lymphocyte analysis, data from first DMF exposure were analyzed. Results: Of 2079 DEFINE/CONFIRM completers, 1736 enrolled and received ⩾1 dose of DMF. The MRI cohort included 530 patients. In the overall population, 527 (30%) patients experienced SAEs; most were fall and urinary tract infection. Over 9 years on DMF treatment, adjusted ARR remained low (⩽0.20). In patients treated with PBO in years 0–2, decreased ARR was apparent as early as year 3. Of DMF/DMF and PBO/DMF patients, 73% and 74%, respectively, had no 24-week confirmed disability progression. Most patients (~70%) had no new T1 or new/newly enlarging T2 lesions compared with previous MRI scans after 7 years treatment with DMF; the annual number of new T1 hypointense lesions and new/newly enlarging T2 hyperintense lesions were 0.6–0.8 and 0.9–2.0, respectively. Mean percentage brain volume change from ENDORSE baseline (6 years treatment in ENDORSE) was −1.32% (range −1.60% to −1.05%). Of the 2513 patients with lymphocyte assessments, 2470 had ⩾1 post-baseline measurement, 53 developed severe prolonged lymphopenia and were followed for up to 11 years; incidence of serious infection was not higher than in patients with absolute lymphocyte count (ALC) always ⩾ lower limit of normal (LLN). In patients with lymphopenia while on DMF and ALC

Background: Multiple sclerosis (MS) is a chronic disease that may require decades of ongoing treatment. Therefore, the long-term safety and efficacy of disease-modifying therapies is an important consideration. Methods: The LONGTERMS study evaluated the safety and efficacy of fingolimod in patients with relapsing MS (RMS) with up to 14 years of exposure. This phase IIIb, open-label extension study included patients aged ⩾ 18 years with confirmed RMS diagnosis who completed previous phase II/III/IIIb core/extension studies of fingolimod. Patients received fingolimod 0.5 mg orally once daily; safety and efficacy (clinical and magnetic resonance imaging) were the main outcomes. Results: Of 4086 patients from the core studies who entered LONGTERMS, 3480 (85.2%) completed the study. The median age (range) was 38 (17–65) years and median fingolimod exposure was 944.5 (range 75–4777) days. Overall, 85.5% of patients experienced at least one adverse event (AE); most common AEs (⩾10%) were viral upper respiratory tract infection (17.3%), headache (13.3%), hypertension (11.0%) and lymphopenia (10.7%). Among patients with serious AEs (12.6%), basal cell carcinoma and MS relapse (0.9% each) were most frequently reported. The aggregate annualized relapse rate decreased from 0.22 (in years 0–2) to 0.17 (years 0–10); 45.5% of patients remained relapse free after 10 years. At year 10, 63.2% of patients were free from 6-month confirmed disability worsening. Conclusion: This long-term observational study of patients treated for up to 14 years with fingolimod confirmed its established safety profile with no new safety concerns. Patients with RMS receiving fingolimod had sustained low levels of disease activity and progression. Trial Registration: ClinicalTrials.gov identifier: NCT01201356.

The cblC defect is the most common inborn error of cobalamin (Cbl) metabolism. Clinical severity and presentation of the cblC defect ranges from death to mild disability. Only 71 cases of late-onset cblC defect have been described in the literature. We provide the 41-year follow up of two siblings with a late-onset cblC defect, first described after initial diagnosis in 1996. While one of the siblings showed initial symptoms resembling multiple sclerosis with a good response to corticosteroids, the other sister showed only subclinical signs of the disease. The course of the first case was characterized by a severe deterioration and intensive-care therapy after respiratory failure. After diagnoses and Cbl treatment, the patient survived and showed a pronounced improvement of the symptoms. Both sisters have an active life and gave birth to healthy children. The reason for the initial improvement after corticosteroids could not be explained by the classical metabolic pathways of Cbl. Recent studies have suggested that Cbl plays an important role as a regulator of the balance between neurotrophic and neurotoxic factors in the central and peripheral nervous system (CNS and PNS). This first long-term follow up revealed that ultra-high-dose intramuscular Hydroxocobalamin (OH-Cbl) treatment can effectively protect patients from disease progression. It underlines the importance of diagnostic vigilance and laboratory work up even in cases without typical hematologic signs of Cbl deficiency. Cbl-related diseases are often a chameleon and must always be considered in the differential of demyelinating diseases of the PNS and CNS. The case supports the theory that it is not only the classical biochemical pathways that play a key role in Cbl deficiency, especially with regard to neurological symptoms.

Objective: To explore the effects of exposure to subcutaneous (sc) interferon (IFN) beta-1a on efficacy in patients with relapsing–remitting multiple sclerosis (RRMS) enrolled in the PRISMS (Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) study. Methods: Patients with RRMS received IFN beta-1a, 44 or 22 µg sc three times weekly (tiw), or placebo, for 2 years, at which point placebo recipients were re-randomized to IFN beta-1a, 44 or 22 µg sc tiw, for a further 2–4 years. Long-term follow-up visits occurred 7–8 years after enrolment and allowed participation of patients who had previously discontinued treatment. Post hoc descriptive analyses were conducted within the lower (MIN) and upper (MAX) quartiles of patients divided according to cumulative dose of IFN beta-1a and cumulative time on treatment. Outcomes were explored in patients initially randomized to IFN beta-1a, 44 µg sc tiw, who had received continuous or noncontinuous therapy during the study. Results: For both cumulative dose and time analyses, the MIN and MAX groups comprised 96 and 95 patients, respectively. The continuous and noncontinuous groups included 45 and 91 patients, respectively. The MAX DOSE and MAX TIME groups had lower annualized relapse rates, lower rates of conversion to secondary progressive MS, lower percentages of patients with Expanded Disability Status Scale progression, higher percentages of relapse-free patients, and less T2 burden of disease than the MIN groups. The continuous therapy group had a lower annualized relapse rate and lower percentages of patients with Expanded Disability Status Scale progression or conversion to secondary progressive MS than the noncontinuous therapy group. Conclusions: The findings of these post hoc analyses suggest that high exposure to sc IFN beta-1a may be associated with better clinical outcomes than low exposure, and also highlight the importance of maximizing adherence. Additional prospective investigation is warranted to evaluate further the effects of treatment exposure on outcomes and to determine the benefits of interventions to improve adherence.