High-efficacy Disease-modifying Therapies Research Articles

Cost-Effectiveness Analysis of Ofatumumab for the Treatment of Relapsing-Remitting Multiple Sclerosis in Canada.

BackgroundOfatumumab is a high-efficacy disease-modifying therapy (DMT) approved for first-line treatment of relapsing-remitting multiple sclerosis (RRMS) in Canada.ObjectiveThe aim of this study was to evaluate the cost effectiveness of ofatumumab from a Canadian healthcare system perspective.MethodsA Markov cohort model was run over 65 years using annual cycles, 1.5% annual discount rate, and 100% treatment discontinuation at 10 years. The British Columbia database informed natural history transition probabilities. Treatment efficacy for DMTs were sourced from a network meta-analysis. Clinical trial data were used to estimate probabilities for treatment-related adverse events. Health utilities and costs were obtained from Canadian sources (if available) and the literature.ResultsAmong first-line indicated therapies for RRMS, ofatumumab was dominant (more effective, lower costs) over teriflunomide, interferons, dimethyl fumarate, and ocrelizumab. Compared with glatiramer acetate and best supportive care, ofatumumab resulted in incremental cost-effectiveness ratios (ICERs) of $24,189 Canadian dollars per quality-adjusted life-year (QALY) and $28,014/QALY, respectively. At a willingness-to-pay threshold of $50,000/QALY, ofatumumab had a 64.3% probability of being cost effective. Among second-line therapies (scenario analysis), ofatumumab dominated natalizumab and fingolimod and resulted in an ICER of $50,969 versus cladribine.ConclusionsOfatumumab is cost effective against all comparators and dominant against all currently approved and reimbursed first-line DMTs for RRMS, except glatiramer acetate.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-022-00363-1.

Multiple sclerosis and COVID-19: Assessing risk perception, patient behaviors and access to disease-modifying therapies

BackgroundFollowing the outbreak of COVID-19, global healthcare systems have had to rapidly adapt. People with multiple sclerosis (pwMS) were required to make decisions about their individual risk and consequent work and social behaviors. This study aimed to evaluate risk perception and patterns of shielding behavior amongst pwMS at the onset of the COVID-19 pandemic and the subsequent impact on patients’ employment and access to disease modifying therapies (DMTs). MethodsPostal surveys were sent to 1690 people within a UK population-based MS cohort during the first wave of the COVID-19 pandemic. Patients were surveyed on: (i) perceived vulnerability to COVID-19; (ii) isolation behavior; (iii) interruption to DMT; (iv) employment status; (v) level of satisfaction with their current working arrangement. ResultsResponses were received from 1000 pwMS. Two thirds of patients reported isolating at home during the first wave of the pandemic. This behavior was associated with increased age (p<0.0001), higher disability (p<0.0001) and use of high-efficacy DMTs (p = 0.02). The majority of patients reported feeling vulnerable (82%) with perceived vulnerability associated with higher EDSS (p<0.0001) and receiving a high-efficacy DMT (p = 0.04). Clinician-defined risk was associated with shielding behavior, with those at high-risk more likely to self-isolate/shield (p<0.0001). Patients on high-efficacy DMTs were more likely to have an interruption to their treatment (50%) during the first wave of the pandemic. Most pwMS experienced a change to their working environment, and most were satisfied with the adjustments. ConclusionThis study highlights the risk perception, social behavioral practices and changes to treatment experienced by pwMS during the first wave of the COVID-19 pandemic in a large, well-described UK cohort. The results may help inform management of pwMS during future pandemic waves.

Multiple Sclerosis and MyChart Messaging: A Retrospective Chart Review Evaluating Its Use.

Understanding patterns of MyChart (Epic Systems Corporation) messaging has the potential to alter clinical practice. However, because most research evaluating its use has been conducted in limited contexts, utilization patterns in patients with multiple sclerosis (MS) remain unclear. We characterized factors associated with high rates of MyChart messaging for patients with MS at an academic outpatient clinic. We performed a retrospective cross-sectional analysis of 439 patients in our center's database. Inclusion criteria were 1 or more clinic visits and MS diagnosis. We extracted demographic data, disease-specific characteristics, and MyChart messaging information. Of the patients in the database, 324 (74%) were MyChart users. MyChart users were more often younger (mean ± SD age, 50.1 ± 12.6 vs 55.0 ± 13.7 years; P < .001), had shorter mean ± SD duration since diagnosis (11.9 ± 8.3 vs 15.8 ± 10.8 years; P = .0013), had lower mean ± SD Patient-Determined Disease Steps scale scores (2.8 ± 2.3 vs 3.5 ± 2.5; P = .0107), and were more likely to be using high-efficacy disease-modifying therapies (χ2 1,323 = 6.7; P = .009). Messaging rates correlated positively with total number of unique medications (R = 0.17; P = .003) and negatively with age (R = -0.11; P = .018). Although previous research has implicated arm-hand disability and impaired vision as barriers to patient portal use, these findings suggest the relationship between MS-specific disease burden and MyChart utilization is also a function of underlying medical complexity beyond physical disability. These data may serve as groundwork for investigations in other disease-specific settings and for quality improvement research to mitigate these high rates in at-risk patients to optimize provider time investment, clinic productivity, and patient safety and minimize health care provider burnout.

Treatment of relapsing multiple sclerosis – recommendations of the Croatian Neurological Society

Untreated multiple sclerosis (MS) irretrievably leads to severe neurological impairment. In European health care systems, patient access to disease modifying therapies (DMT) is often confined to more advanced stages of the disease because of restrictions in reimbursement. A discrepancy in access to DMTs is evident between West and East European countries. In order to improve access to DMTs for people with MS (pwMS) living in Croatia, the Croatian Neurological Society issued new recommendations for the treatment of relapsing MS. The aim of this article is to present these recommendations. The recommendations for platform therapies are to start DMT as soon as the diagnosis is made. If poor prognostic criteria are present (≥9 T2 or FLAIR lesions on the initial brain and spinal cord magnetic resonance imaging [MRI] or ≥3 T1 lesions with postcontrast enhancement on the initial brain and spinal cord MRI or Expanded Disability Status Scale after treatment of the initial relapse ≥3), high-efficacy DMT should be initiated. If pwMS experience ≥1 relapse or ≥3 new T2 lesions while on platform therapies, they should be switched to high-efficacy DMT. Further efforts should be made to enable early and unrestricted access to high-efficacy DMT with a freedom of choice of an appropriate therapy for expert physicians and pwMS. The improvement of access to DMT achieved by the implementation of national treatment guidelines in Croatia can serve as an example to national neurological societies from other Eastern European countries to persuade payers to enable early and unrestricted treatment of pwMS.

Treatment with natalizumab during pregnancy in multiple sclerosis: The experience of implementing a clinical practice protocol (NAP-30)

BackgroundPregnancy planning in women with highly active multiple sclerosis (HAMS) who need a high-efficacy disease-modifying therapy (heDMT) currently requires a careful risk-benefit evaluation. This includes minimizing fetal drug toxicity and preventing MS reactivation. We describe our experience with natalizumab in women with HAMS and unplanned pregnancy by implementing a clinical practice protocol (NAP-30) designed to maintain the effectiveness of natalizumab during pregnancy, reduce fetal exposure and prevent complications. MethodsThis was an observational retrospective study including women with HAMS on active treatment with natalizumab who became unexpectedly pregnant in the period 2018–2021 and continued this treatment during pregnancy according to the NAP-30 protocol. MS clinical and radiological variables were analyzed before and during pregnancy and in the postpartum period, along with maternal and fetal toxicity during pregnancy and safety findings in newborns. We also describe the NAP-30 protocol, which includes the use of a bridging dose to adjust and maintain natalizumab infusions every 6 weeks during pregnancy up to week 30 and scheduled delivery at week 40. ResultsSix women (one in her first gestation) with a median age of 31.5 years at the onset of pregnancy (min-max: 24–37 years) were included. All were negative for anti-John Cunningham virus (JCV) antibodies and were on treatment with intravenous natalizumab 300 mg every 4 weeks. At the time of conception, three patients had received 12, 17 and 53 infusions of natalizumab, respectively, while for the remaining three patients natalizumab was their first DMT (two patients had received 6 infusions and one patient had received 3 infusions of natalizumab). All six patients received 6 doses of natalizumab during pregnancy according to the NAP-30 protocol. After delivery, all six patients restarted natalizumab every 4 weeks (median: 3 days; range: 2–4 days). No patients had relapses during pregnancy or at 6 months postpartum, nor did they develop any general health or laboratory abnormalities. The MRI scan performed at 4–6 months postpartum showed no new T2 lesions or gadolinium-enhancing lesions. No miscarriages or threatened miscarriages were reported. One of the patients underwent elective preterm delivery at week 35 after mild-to-moderate anemia was detected by fetal Doppler scan. The newborn had low birth weight (2080 g) and mild anemia, which resolved within two months with oral iron supplementation. The other infants were born with normal birth weight and showed no blood count abnormalities. After a median follow-up of 10 months, all six babies showed normal development with no complications detected. ConclusionsBased on our experience, the implementation of the NAP-30 protocol in women with HAMS and unplanned pregnancy undergoing treatment with natalizumab allows the continuation of natalizumab during pregnancy, with a very favorable clinical and radiological effectiveness and maternal-fetal safety profile during pregnancy and postpartum. Both in pregnancy with HAMS and in general, and particularly for successful implementation of the NAP-30 protocol, obstetric support and monitoring is essential for adequate pregnancy management.

Comparative safety of high-efficacy disease-modifying therapies in relapsing-remitting multiple sclerosis: a systematic review and network meta-analysis.

This study aimed to compare the safety profile of high-efficacy disease-modifying therapies (DMTs) natalizumab, fingolimod, alemtuzumab, cladribine, ocrelizumab, ofatumumab, ozanimod, as well as a potentially high-efficacy DMT, ponesimod, in adult patients with relapsing-remitting multiple sclerosis (RRMS). A systematic review with frequentist network meta-analysis (NMA) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We included randomized controlled trials (RCTs) with at least 48-week follow-up investigating the use of natalizumab, fingolimod, alemtuzumab, cladribine, ocrelizumab, ofatumumab, ozanimod, and ponesimod, as well as other DMTs, in adult patients with RRMS. Eligible studies were identified by two reviewers in MEDLINE (via PubMed), EMBASE, and Cochrane Library. The Cochrane Collaboration tool to assess the risk of bias for RCTs was used. A total of 33 RCTs were included in the systematic review and NMA. A higher rate of adverse events (AEs) was revealed for alemtuzumab versus all other high-efficacy DMTs; for alemtuzumab (average probability of an event: 98.2%) versus placebo (86.2%); for cladribine (3.5mg; 90.5%) versus ozanimod (1mg; 84.2%) and placebo; as well as for ocrelizumab (95.5%) versus ozanimod, ofatumumab (88.9%), fingolimod (87.4%), natalizumab (82.8%), and placebo. No significant differences were found between drugs in terms of serious AEs except for cladribine (3.5mg, 17.3%) versus ocrelizumab (10.3%) and ofatumumab (16.6%) versus ocrelizumab. Significant differences in AEs leading to the discontinuation of study drug were found only for ponesimod (10.1%) versus alemtuzumab (12mg, 3.0%) and placebo (4.2%). No differences were found in terms of upper respiratory tract infections, nasopharyngitis, fatigue, and nausea between individual high-efficacy DMTs as well as between DMTs and placebo. The results of the NMA indicated a higher risk of infections for alemtuzumab (12mg) versus ocrelizumab, for cladribine (3.5mg) versus ofatumumab and placebo, and for ofatumumab versus placebo. For serious infections and urinary tract infections, a significant increase was found only for alemtuzumab (12mg) versus ocrelizumab, while no differences were found between the other DMTs or between DMTs and placebo. Headache was more common for alemtuzumab (12mg) as compared with all the other high-efficacy DMTs and placebo, as well as for cladribine versus natalizumab and fingolimod versus natalizumab. The commonly reported AEs are generally similar among high-efficacy DMTs. However, based on P scores for most analyzed endpoints, natalizumab and ocrelizumab were shown to be the safest DMTs. Considering the limitations of indirect comparisons, further research is needed to confirm our findings, preferably head-to-head RCTs and large observational studies.

The effect of timing of high-efficacy therapy on processing speed performance in multiple sclerosis

BackgroundThe potential influence of the timing of high-efficacy disease-modifying therapies (heDMTs) on processing speed (PS) performance is critically lacking in current literature. ObjectiveTo assess the extent to which early commencement of heDMTs would be associated with a better PS evolution as compared to moderate efficacy disease-modifying therapies (meDMTs) and delayed commencement of heDMTs. MethodsIn this ongoing prospective longitudinal study, the 695 MS patients that have received a PS evaluation at 12-month of follow-up measured by the iPad®-based Processing Speed Test (PST) were retained for the analysis. All patients who had ever been prescribed a high efficacy disease-modifying therapy (heDMT) were classified in tertiles according to the proportion of their disease duration that had been on heDMTs. Based on these tertiles and the time to the first heDMT from the disease onset, patients were divided into the early heDMT group and the delayed heDMT group. Between-group differences in mean PST standardized (Z-score) change from baseline were analyzed using a linear mixed model. ResultsIn the multivariable model, each year of delay in starting a heDMT was associated with increased odds of cognitive worsening at 12-month (OR = 1.0324, 95% CI = 1.014-1.062, p<0.05). MeDMT-treated patients were at a significantly higher risk for cognitive worsening than early heDMT patients (OR= 2.57, 95%CI = 1.02-6.17). Linear mixed model-based adjusted mean change in PST Z-score from baseline was significantly better in those patients with the longest proportion of their disease duration treated with heDMT (highest tertile) compared to the lowest tertile (difference 0.37 [95%CI 0.02-0.92;p=0.036) and medium tertile (difference 0.39 [95%CI 0.06-0.31;p=0.037). ConclusionEarly he-DMT-treated patients are at significantly lower risk for cognitive worsening. Early administration of heDMTs is associated with greater cognitive functioning improvements than delayed commencement or meDMTs.

Implementing education: Personal communication with a healthcare professional is a critical step to address vaccine hesitancy for people with multiple sclerosis

BackgroundPeople with Multiple Sclerosis (PwMS) were first able to access COVID-19 vaccines in Australia from March 2021, when vaccine hesitancy in the general population was high (14–43%). High uptake of vaccination is important globally and critical to protect this vulnerable population. We conducted an on-line survey to examine factors influencing COVID-19 vaccination willingness among PwMS in Australia. Methods149 PwMS living in Australia completed the on-line survey (April-September 2021) examining demographic, environmental and clinical factors with respect to vaccine willingness, including attitudes towards COVID-19 illness and vaccines. Additional items explored the influence of different information sources on vaccination decisions. Continuous and ordinal data were compared using the Mann-Whitney U test. All tests were two-tailed, with alpha set at 0.5. ResultsA majority of the respondents were female (87.2%) with relapsing-remitting MS (77.5%) treated by a neurologist (94.0%). A majority were on high efficacy disease-modifying therapies (DMTs) (64.9%), while 19.9% were on no DMTs. About one third of respondents (32.9%) had had two doses, 20.8% had received their first dose, and 22.1% were unvaccinated, while 24.2% of responses were missing. When asked about vaccine intentions, 60.6% of the unvaccinated indicated they were likely to extremely likely to get vaccinated, while 15.2% were very unlikely or extremely unlikely to do so and 24.2% were undecided. Unvaccinated people were significantly more concerned about vaccine side effects (mean 5.3 versus 3.1/10; p < .001). Only 53.3% of people on DMTs were vaccinated, compared to 75% of those who were not. People on ocrelizumab therapy (n = 35) had a lower vaccination rate (39%) than those on other medications (n = 86, 59%). Vaccine willingness in the unvaccinated was most highly correlated with knowledge regarding the vaccine (rs2=.709), agreement with the statement that COVID-19 vaccination is “too new for me to be confident about getting vaccinated” (rs2= -.709), anticipation of regret due to side effects of vaccination (rs2= -.642), and lack of knowledge regarding interactions between COVID-19 vaccines and DMTs (rs2= -.570).Almost two thirds had read MS-specific information about COVID-19 vaccinations and found it easy to understand (67.6%) and applicable to their situation (53.6%). However, less than half (47.8%) reported the information helped them make a personal vaccination decision. Over two-thirds (64.9%) had discussed vaccinations with their healthcare professional and 31.1% had not. Those who had not, were significantly more uninformed about the interactions of the vaccine with MS medications (mean 3.9 versus 2.9/10; p = .044) and significantly lower intention of vaccine uptake than those who had (mean 5.8 versus 7.9/10; p = .009). ConclusionOur study highlights that vaccination efforts should be delivered by healthcare professionals, focus on educating those who are managed with DMTs, and include individual recommendations related to specific DMTs, how the vaccines work, expectations regarding potential side-effects, potential exacerbation of MS symptoms, likelihood of recovery from any exacerbation, and the relative risks of side effects versus COVID-19 infection. Specific recommendations are provided.

Interrogating large multiple sclerosis registries and databases: what information can be gained?

Although substantial progress has been made in understanding the natural history of multiple sclerosis (MS) and the development of new therapies, many questions concerning disease behavior and therapeutics remain to be answered. Data generated from real-world observational studies, based on large MS registries and databases and analyzed with advanced statistical methods, are offering the scientific community answers to some of these questions that are otherwise difficult or impossible to address. This review focuses on observational studies published in the last 2 years designed to compare the effectiveness of escalation vs. induction treatment strategies, to assess the effectiveness of treatment in pediatric-onset and late-onset MS, and to identify the clinical phenotype of secondary progressive (SP)MS. The main findings originating from real-world studies suggest that MS patients who will qualify for high-efficacy disease-modifying therapies (DMTs) should be offered these as early as possible to prevent irreversible accumulation of neurological disability. Especially pediatric patients derive substantial benefits from early treatment. In patients with late-onset MS, sustained exposure to DMTs may result in more favorable outcomes. Data-driven definitions are more accurate in defining transition to SPMS than diagnosis based solely on neurologists' judgment. Patients, physicians, industry, and policy-makers have all benefited from real-world evidence based on registry data, in answering questions of diagnostics, choice of treatment, and timing of treatment decisions.

Early use of high-efficacy disease‑modifying therapies makes the difference in people with multiple sclerosis: an expert opinion

Multiple sclerosis (MS) is a chronic and progressive neurological disease that is characterized by neuroinflammation, demyelination and neurodegeneration occurring from the earliest phases of the disease and that may be underestimated. MS patients accumulate disability through relapse-associated worsening or progression independent of relapse activity. Early intervention with high-efficacy disease-modifying therapies (HE-DMTs) may represent the best window of opportunity to delay irreversible central nervous system damage and MS-related disability progression by hindering underlying heterogeneous pathophysiological processes contributing to disability progression. In line with this, growing evidence suggests that early use of HE-DMTs is associated with a significant greater reduction not only of inflammatory activity (clinical relapses and new lesion formation at magnetic resonance imaging) but also of disease progression, in terms of accumulation of irreversible clinical disability and neurodegeneration compared to delayed HE-DMT use or escalation strategy. These beneficial effects seem to be associated with acceptable long-term safety risks, thus configuring this treatment approach as that with the most positive benefit/risk profile. Accordingly, it should be mandatory to treat people with MS early with HE-DMTs in case of prognostic factors suggestive of aggressive disease, and it may be advisable to offer an HE-DMT to MS patients early after diagnosis, taking into account drug safety profile, disease severity, clinical and/or radiological activity, and patient-related factors, including possible comorbidities, family planning, and patients’ preference in agreement with the EAN/ECTRIMS and AAN guidelines. Barriers for an early use of HE-DMTs include concerns for long-term safety, challenges in the management of treatment initiation and monitoring, negative MS patients’ preferences, restricted access to HE-DMTs according to guidelines and regulatory rules, and sustainability. However, these barriers do not apply to each HE-DMT and none of these appear insuperable.

High Levels of Cerebrospinal Fluid Kappa Free Light Chains Relate to IgM Intrathecal Synthesis and Might Have Prognostic Implications in Relapsing Multiple Sclerosis.

Cerebrospinal kappa free light chain (KFLC)-index is a marker of intrathecal immunoglobulin synthesis that aids in the diagnosis of multiple sclerosis (MS). However, little evidence exists on its prognostic role. Our aim is to analyze the relationship between KFLC-index and other MS biomarkers and to explore its prognostic role. This is a monocentric observational study in a cohort of 52 people with relapsing MS (pwRMS) performed on prospectively acquired clinical data and with retrospective evaluation of biomarkers. We measured KFLC-index, immunoglobulin intrathecal synthesis, cerebrospinal fluid (CSF) chitinase 3-like 1 (CHI3L1), and neurofilament light protein (NFL) and reviewed MRI to detect leptomeningeal contrast enhancement (LMCE). We compared time to Expanded Disability Status Scale (EDSS) 3 and to initiation of high-efficacy disease-modifying therapies (heDMTs) by multivariate Cox regression analysis. Median KFLC-index correlated with IgG/IgM indexes (p < 0.0001/p < 0.05) and IgG-oligoclonal bands (OCGBs) (p < 0.001). Patients with IgM-oligoclonal bands (OCMBs) had a higher KFLC-index (p = 0.049). KFLC-index was higher in patients with LMCE (p = 0.008) and correlated with CHI3L1 (p = 0.007), but disease activity had no effect on its value. Bivariate and multivariate analyses confirmed KFLC-index > 58 as an independent risk factor for reaching an EDSS of 3 (hazard ratio (HR) = 12.4; 95% CI = 1.1–147; p = 0.047) and for the need of treatment with heDMTs (HR = 3.0; 95% CI = 1.2–7.1; p = 0.0013). To conclude, our data suggest a potential prognostic role of the KFLC-index during the MS course.

Medication Adherence Among Patients with Multiple Sclerosis During the COVID-19 Pandemic: Perspective from the Near East Region

Background: Several factors rendered patients with multiple sclerosis (pwMS) likely to be affected by the rapidly evolving events of the COVID-19 pandemic. Globally, pwMS were confronted with limited access to their healthcare team, potential treatment interruption, and concerns about the risk of infection while treated with immunomodulatory disease-modifying therapies (DMTs), particularly high-efficacy DMTs. The current study explored treatment-related concerns and their impact on medication adherence during the COVID-19 pandemic in pwMS treated with subcutaneous interferon beta-1a (sc IFN β-1a) in the Near East region.

Claims-Based Relapse and Hospitalization Rates in Patients with Multiple Sclerosis Treated with Natalizumab or Ocrelizumab

Background: Natalizumab (NTZ) and ocrelizumab (OCR) are high-efficacy disease-modifying therapies (DMTs) approved to treat relapsing forms of multiple sclerosis (MS). Real-world head-to-head data comparing relapses and related hospitalization rates for high-efficacy DMTs, including NTZ vs OCR, are limited. To compare claims-based relapses and relapse-related hospitalization rates for MS patients treated with NTZ or OCR using data from a large insurance claims database.

Safety of Fingolimod in Patients with Multiple Sclerosis Switched from Natalizumab: Results from TRANSITION-A 2-Year, Multicenter, Observational, Cohort Study.

Multiple sclerosis (MS) patients receiving natalizumab and who are at risk of developing progressive multifocal leukoencephalopathy (PML) often switch to other high-efficacy disease-modifying therapies including fingolimod as a risk mitigation strategy, which could impact treatment safety and effectiveness. The TRANSITION study aimed to evaluate the safety of fingolimod over two years in patients with MS after switching from natalizumab in a real-world setting. The safety and effectiveness were assessed by monitoring serious and other adverse events (SAEs, AEs). We assessed effectiveness by recording relapses, Expanded Disability Status Scale (EDSS) scores, and MRI activity. Of 637 patients enrolled, 505 completed the study (mean age, 42 years). Overall, 72.8% and 12.7% experienced AEs and SAEs respectively. The most common AEs were fatigue, headache, and urinary tract infection; no cases of PML were observed. Fingolimod treatment resulted in low disease activity. Patients with ≤8 weeks washout period had a markedly lower risk of relapses (4.5%) than those with >8 weeks (51.4%). In patients switching from natalizumab to fingolimod, no new safety signals with overall low relapse activity were observed in patients with washout latencies of ≤8 weeks before fingolimod initiation. Fingolimod was found to be safe and effective in patients transitioning from natalizumab.

Ocrelizumab: A Review in Multiple Sclerosis.

Ocrelizumab (Ocrevus®) is an intravenously administered, humanized anti-CD20 monoclonal antibody approved for the treatment of adults with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The efficacy of ocrelizumab in reducing relapse rates and disease activity in patients with RMS was demonstrated in pivotal trials (versus interferon β-1a) and supporting single-arm studies in specific subpopulations. In patients with PPMS, ocrelizumab reduced measures of clinical and MRI progression relative to placebo. Clinical benefits were maintained over ≥ 7.5 study years of treatment. Ocrelizumab was generally well tolerated and no new safety signals have emerged with long-term use. Extensive (albeit short-term) real-world data pertaining to ocrelizumab is consistent with that from clinical trials. Ocrelizumab provides the convenience of short, half-yearly infusions. Ocrelizumab continues to represent a generally well-tolerated, high-efficacy disease-modifying therapy (DMT) for RMS and is a valuable treatment for delaying disease progression in patients with PPMS (for whom there are currently no other approved DMTs).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40265-022-01672-9.

Evolution of Disease Modifying Therapy Benefits and Risks: An Argument for De-escalation as a Treatment Paradigm for Patients With Multiple Sclerosis

BackgroundStrategies for sequencing disease modifying therapies (DMTs) in multiple sclerosis (MS) patients include escalation, high efficacy early, induction, and de-escalation.ObjectiveTo provide a perspective on de-escalation, which aims to match the ratio of DMT benefit/risk in aging patients.MethodsWe reanalyzed data from a retrospective, real-world cohort of MS patients to model disease activity for oral (dimethyl fumarate and fingolimod) and higher efficacy infusible (natalizumab and rituximab) DMTs by age. For patients with relapsing MS, we conducted a controlled, stratified analysis examining odds of disease activity for oral vs. infusible DMTs in patients <45 or ≥45 years. We reviewed the literature to identify DMT risks and predictors of safe discontinuation.ResultsYounger patients had lower probability of disease activity on infusible vs. oral DMTs. There was no statistical difference after age 54.2 years. When dichotomized, patients <45 years on oral DMTs had greater odds of disease activity compared to patients on infusible DMTs, while among those ≥45 years, there was no difference. Literature review noted that adverse events increase with aging, notably infections in patients with higher disability and longer DMT duration. Additionally, we identified factors predictive of disease reactivation including age, clinical stability, and MRI activity.ConclusionIn a real-world cohort of relapsing MS patients, high efficacy DMTs had less benefit with aging but were associated with increased risks. This cohort helps overcome some limitations of trials where older patients were excluded. To better balance benefits/risks, we propose a DMT de-escalation approach for aging MS patients.

Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment.

Pediatric-onset multiple sclerosis (POMS) is a rare neuroinflammatory and neurodegenerative disease that has a significant impact on long-term physical and cognitive patient outcomes. A small percentage of multiple sclerosis (MS) diagnoses occur before the age of 18 years. Before treatment initiation, a careful differential diagnosis and exclusion of other similar acquired demyelinating syndromes such as anti-aquaporin-4-associated neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody spectrum disorder (MOGSD) is warranted. The recent 2017 changes to the McDonald criteria can successfully predict up to 71% of MS diagnoses and have good specificity of 95% and sensitivity of 71%. Additional measures such as the presence of T1-weighted hypointense lesions and/or contrast-enhancing lesions significantly increase the accuracy of diagnosis. In adults, early use of disease-modifying therapies (DMTs) is instrumental to a better long-term prognosis, including lower rates of relapse and disability worsening, and numerous FDA-approved therapies for adult-onset MS are available. However, unlike their adult counterparts, the development, testing, and regulatory approval of POMS treatments have been significantly slower and hindered by logistic and/or ethical considerations. Currently, only two MS DMTs (fingolimod and teriflunomide) have been tested in large phase III trials and approved by regulatory agencies for use in POMS. First-line therapies not approved by the FDA for use in children (interferon-β and glatiramer acetate) are also commonly used and result in a significant reduction in inflammatory activity when compared with non-treated POMS patients. An increasing number of POMS patients are now treated with moderate efficacy therapies such as dimethyl fumarate and high-efficacy therapies such as natalizumab, anti-CD20 monoclonal antibodies, anti-CD52 monoclonal antibodies, and/or autologous hematopoietic stem cell transplantation. These high-efficacy DMTs generally provide additional reduction in inflammatory activity when compared with the first-line medications (up to 62% of relapse-rate reduction). Therefore, a number of phase II and III trials are currently investigating their efficacy and safety in POMS patients. In this review, we discuss potential changes in the regulatory approval process for POMS patients that are recommended for DMTs already approved for the adult MS population, including smaller sample size for pharmacokinetic/pharmacodynamic studies, MRI-centered primary outcomes, and/or inclusion of teenagers in the adult trials.

Humoral immune response in convalescent COVID-19 people with multiple sclerosis treated with high-efficacy disease-modifying therapies: A multicenter, case-control study

AimTo determine the influence of high-efficacy disease modifying therapy (DMT) on the development of IgG SARS-CoV-2 antibody response in COVID-19 convalescent people with multiple sclerosis (pwMS). MethodsSeventy-four pwMS taking high-efficacy DMTs (specifically natalizumab, fingolimod, alemtuzumab, ocrelizumab, cladribine and ublituximab) and diagnosed with COVID-19 and 44 healthy persons (HC) were enrolled. SARS-CoV2 antibodies were tested with Elecsys® Anti-SARSCoV-2 S assay. ResultspwMS taking high-efficacy DMTs had a significantly higher chance of having negative titer of SARS-CoV2 antibodies compared to healthy controls (33 negative pwMS [44.6%] compared to one negative HC [2.3%], p < 0.001). pwMS taking B-cell depleting therapy (ocrelizumab and ublituximab) had a significantly higher chance of having negative titer of SARS-CoV2 antibodies compared to pwMS on all other DMTs (29 negative pwMS on B-cell therapy [64.4%] compared to four negative pwMS on all other DMTs [13.8%], p < 0.001). Out of other DMTs, two (33.3%) pwMS taking fingolimod and two (16.7%) pwMS taking cladribine failed to develop IgG SARS-COV-2 antibodies. B-cell depleting therapy independently predicted negative titer of IgG SARS-CoV-2 antibody (Exp[B] =0.014, 95%CI 0.002–0.110, p < 0.001). ConclusionsA significant proportion of convalescent COVID-19 pwMS on high-efficacy DMTs will not develop IgG SARS-CoV-2 antibodies. B-cell depleting therapies independently predict negative and low titer of IgG SARS-CoV-2 antibody.

Initial treatment strategy and clinical outcomes in Finnish MS patients: a propensity-matched study

BackgroundThe optimal treatment strategy with disease-modifying therapies (DMTs) in relapsing–remitting multiple sclerosis (RRMS) remains uncertain.ObjectiveTo compare outcomes of initial treatment with infusion therapies and starting therapy with medium efficacy therapy in a propensity-matched cohort of Finnish RRMS patients.MethodsA total of 154 RRMS patients initiating natalizumab, alemtuzumab, ocrelizumab or rituximab as first DMT (high efficacy DMT, heDMT group) and 1771 patients initially treated with injectable therapies, teriflunomide or dimethylfumarate and escalated based on disease activity (moderate efficacy DMT, meDMT group) were identified from the Finnish MS registry. Nearest neighbor propensity matching (1:1, caliper 0.1) was performed for age, sex, baseline Expanded Disability Status Scale (EDSS), annual relapse rate (ARR) one year prior DMT and time since MS symptom onset. Primary outcome was time to 6-month confirmed EDSS progression and the secondary outcome time to first relapse.ResultsIn the propensity-matched group comparisons, the probability of 6-month confirmed disability progression (CDP) at 5 years after DMT start was 28.4% (95% CI 15.7–39.3) in the heDMT group (n = 66) and 47.0% (95% CI 33.1–58.1) in meDMT group (n = 66), p = 0.013. Probability of relapse at 5 years was 34.6% (95% CI 24.1–43.6) for heDMT (n = 105) and 47.2% (95% CI 36.6–56.1) for meDMT (n = 105), p = 0.019.ConclusionsInitiating MS-therapy with heDMT significantly reduced the risk of 5-year disability progression and relapse compared to using meDMT as first DMT choice in propensity-matched groups of Finnish MS-patients.

Early High Efficacy Treatment in Multiple Sclerosis Is the Best Predictor of Future Disease Activity Over 1 and 2 Years in a Norwegian Population-Based Registry.

Background: Moderate and high efficacy disease modifying therapies (DMTs) have a profound effect on disease activity. The current treatment guidelines only recommend high efficacy DMTs for patients with highly active MS. The objective was to examine the impact of initial treatment choice in achieving no evidence of disease activity (NEDA) at year 1 and 2.Methods: Using a real-world population-based registry with limited selection bias from the southeast of Norway, we determined how many patients achieved NEDA on moderate and high efficacy DMTs.Results: 68.0% of patients who started a high efficacy DMT as the first drug achieved NEDA at year 1 and 52.4% at year 2 as compared to 36.0 and 19.4% of patients who started a moderate efficacy DMT as a first drug. The odds ratio (OR) of achieving NEDA on high efficacy drugs compared to moderate efficacy drugs as a first drug at year 1 was 3.9 (95% CI 2.4–6.1, p < 0.001). The OR for high efficacy DMT as the second drug was 2.5 (95% CI 1.7–3.9, p < 0.001), and was not significant for the third drug. Patients with a medium or high risk of disease activity were significantly more likely to achieve NEDA on a high efficacy therapy as a first drug compared to moderate efficacy therapy as a first drug.Conclusions: Achieving NEDA at year 1 and 2 is significantly more likely in patients on high-efficacy disease modifying therapies than on moderate efficacy therapies, and the first choice of treatment is the most important. The immunomodulatory treatment guidelines should be updated to ensure early, high efficacy therapy for the majority of patients diagnosed with MS.