Treatment switches of disease-modifying therapies in people with multiple sclerosis: long-term experience from the German MS Registry.

Background: The spectrum of disease-modifying therapies (DMTs) for people with multiple sclerosis (PwMS) has expanded over years, but data on treatment strategies is largely lacking. DMT switches are common clinical practice. Objective: To compare switchers and non-switchers, characterize the first DMT switch and identify reasons and predictors for switching the first DMT. Methods: Data on 2722 PwMS from the German MS Registry were retrospectively analyzed regarding sociodemographic/clinical differences between 1361 switchers (PwMS discontinuing the first DMT) and non-switchers matched according to age, sex, and observation period. Frequencies of first and second DMTs were calculated and switch reasons identified. Predictors for DMT switches were revealed using univariable and multivariable regression models. Results: Switchers and non-switchers differed significantly regarding time to first DMT, education, calendar period of the first DMT start (2014-2017 versus 2018-2021), first DMT class used [mild-to-moderate efficacy (MME) versus high-efficacy (HE) DMT], time on first DMT, and disease activity at first DMT start or cessation/last follow-up. The majority of PwMS started with MME DMTs (77.1%), with the most common being glatiramer acetate, dimethyl/diroximel fumarate, and beta-interferon variants. Switchers changed treatment more often to HE DMTs (39.6%), most commonly sphingosine-1-phosphate receptor modulators, anti-CD20 monoclonal antibodies, and natalizumab. Fewer PwMS switched to MME DMTs (35.9%), with the most common being dimethyl/diroximel fumarate, teriflunomide, or beta-interferon. Among 1045 PwMS with sufficient data (76.8% of 1361 switchers), the most frequent reasons for discontinuing the first DMT were disease activity despite DMT (63.1%), adverse events (17.1%), and patient request (8.3%). Predictors for the first DMT switch were MME DMT as initial treatment [odds ratio (OR) = 2.83 (1.76-4.61), p < 0.001; reference: HE DMT], first DMT initiation between 2014 and 2017 [OR = 11.55 (6.93-19.94), p < 0.001; reference: 2018-2021], and shorter time on first DMT [OR = 0.22 (0.18-0.27), p < 0.001]. Conclusion: The initial use of MME DMTs was among the strongest predictors of DMT discontinuation in a large German retrospective MS cohort, arguing for the need for prospective treatment strategy trials, not only but also on the initial broad use of HE DMTs in PwMS.

Real-world persistence of multiple sclerosis disease-modifying therapies.

BACKGROUND AND PURPOSE: Treatment persistence is the continuation of therapy over time. It reflects a combination of treatment efficacy and tolerability. We aimed to describe real-world rates of persistence on disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS) and reasons for DMT discontinuation. METHODS: Treatment data on 4366 consecutive people with relapse-onset multiple sclerosis (MS) were pooled from 13 UK specialist centres during 2021. Inclusion criteria were exposure to at least one MS DMT and a complete history of DMT prescribing. PwMS in blinded clinical trials were excluded. Data collected included sex, age at MS onset, age at DMT initiation, DMT treatment dates, and reasons for stopping or switching DMT. For pwMS who had received immune reconstituting therapies (cladribine/alemtuzumab), discontinuation date was defined as starting an alternative DMT. Kaplan-Meier survival analyses were used to express DMT persistence. RESULTS: In 6997 treatment events (1.6 per person with MS), median time spent on any single maintenance DMT was 4.3 years (95% confidence interval = 4.1-4.5 years). The commonest overall reasons for DMT discontinuation were adverse events (35.0%) and lack of efficacy (30.3%). After 10 years, 20% of people treated with alemtuzumab had received another subsequent DMT, compared to 82% of people treated with interferon or glatiramer acetate. CONCLUSIONS: Immune reconstituting DMTs may have the highest potential to offer a single treatment for relapsing MS. Comparative data on DMT persistence and reasons for discontinuation are valuable to inform treatment decisions and in personalizing treatment in MS.

Treatment patterns and persistence on disease modifying therapies for multiple sclerosis and its associated factors.

BACKGROUND: Effective interventions for Multiple Sclerosis require timely treatment optimization which usually involves switching disease modifying therapies. The patterns of prescription and the reasons for changing treatment in people with MS, especially in low prevalence populations, are unknown. OBJECTIVES: To describe the persistence, reasons of DMT switches and prescription patterns in a cohort of Colombian people with MS. METHODS: We conducted a retrospective observational study including patients with confirmed MS with at least one visit at our centre. We estimated the overall incidence rate of medication changes and assessed the persistence on medication with Kaplan-Meier survival estimates for individual medications and according to efficacy and mode of administration. The factors associated with changing medications were assessed using adjusted Cox proportional-hazards models. The reasons for switching medication changes were described, and the prescription patterns were assessed using network analysis, with measures of centrality. RESULTS: Seven hundred one patients with MS were included. Mean age was 44.3 years, and 67.9% were female. Mean disease duration was 11.3 years and 84.5% had relapsing MS at onset, with median EDSS of 1.0. Treatment was started in 659 (94%) of the patients after a mean of 3 years after MS symptom onset. Among them, 39.5% maintained their initial DMT, 29.9% experienced a single DMT change, while 18.7% went through two, and 11.9% had three or more DMT changes until the final follow-up. The total number of treatment modifications reached 720, resulting in an incidence rate of 1.09 (95% confidence interval: 1.01-1.17) per patient per year The median time to change after the first DMT was 3.75 years, and was not different according to the mode of administration or efficacy classification. The main reasons for changing DMT were MS activity (relapses, 56.7%; MRI activity, 18.6%), followed by non-serious adverse events (15.3%) and disability (11.1%). Younger age at MS onset, care under our centre and insurer status were the main determinants of treatment change. Network analysis showed that interferons and fingolimod were the most influential DMTs. CONCLUSIONS: A majority of patients switch medications, mostly due to disease activity, and in association with age and insurer status.

SARS-CoV-2 infection increases long-term multiple sclerosis disease activity and all-cause mortality in an underserved inner-city population.

BACKGROUND: Although certain subsets patients with multiple sclerosis (MS), an immune-mediated disorder, are at higher risk of worse acute COVID-19 outcomes compared to the general population, it is not clear whether SARS-CoV-2 infection impacts long-term outcomes compared with MS patients without COVID-19 infection. OBJECTIVES: This study investigated MS disease activity and mortality 3.5 years post SARS-CoV-2 infection and compared with MS patients without COVID-19. METHODS: This retrospective study evaluated 1,633 patients with MS in the Montefiore Health System in the Bronx from January 2016 to July 2023. This health system serves a large minority population and was an epicenter for the early pandemic and subsequent surges of infection. Positive SARS-CoV-2 infection was determined by a positive polymerase-chain-reaction test. Primary outcomes were all-cause mortality, and optic neuritis post SARS-CoV-2 infection. Secondary outcomes included change in disease-modifying therapy (DMT), treatment with high-dose methylprednisolone, cerebellar deficits, relapse, and all-cause hospitalization post-infection. RESULTS: MS patients with COVID-19 had similar demographics but higher prevalence of pre-existing major comorbidities (hypertension, type-2 diabetes, chronic obstructive pulmonary disease, congestive heart failure, chronic kidney disease, and coronary artery disease), optic neuritis, and history of high dose steroid treatment for relapses compared to MS patients without COVID-19. MS patients with COVID-19 had greater risk of mortality (adjusted HR=4.34[1.67, 11.30], p < 0.005), greater risk of post infection optic neuritis (adjusted HR=2.97[1.58, 5.58], p < 0.005), higher incidence of methylprednisolone treatment for post infection acute relapse (12.65% vs. 2.54 %, p < 0.001), and more hospitalization (78.92% vs. 66.81 %, p < 0.01), compared to MS patients without COVID-19. CONCLUSIONS: MS patients who survived COVID-19 infection experienced worse long-term outcomes, as measured by treatment for relapse, hospitalization and mortality. Identifying risk factors for worse long-term outcomes may draw clinical attention to the need for careful follow-up of at-risk individuals post-SARS-CoV-2 infection.

Treatment algorithms of relapsing multiple sclerosis: an exploration based on the available disease-modifying therapies in China.

Multiple sclerosis (MS) was defined as a rare disease in China due to its low prevalence. For a long time, interferon ß was the only approved disease-modifying therapy (DMT). Since the first oral DMT was approved in 2018, DMT approval accelerated, and seven DMTs were approved within 5 years. With an increasing number of DMTs being prescribed in clinical practice, it is necessary to discuss the standardized MS treatment algorithms depending on the disease activity and DMT availability. In this review paper, more than 20 Chinese experts in MS have reviewed the therapeutic progress of MS in China and worldwide and discussed algorithms for treating relapsing MS (RMS) based on the available DMTs in China, providing insights for establishing the standardized RMS treatment algorithms in this country.

Treatment algorithms of relapsing multiple sclerosis in China In this review paper, more than 20 Chinese experts in MS have reviewed the therapeutic progress of MS in China and worldwide and discussed algorithms for treating relapsing MS (RMS) based on the available DMTs in China, providing insights for establishing the standardized RMS treatment algorithms in this country: 1) CIS and RRMS account for more than 90% of the MS patients and most of them are mild to moderate; 2) MS patients should initiate DMT treatments as soon as the disease has been diagnosed in order to reduce the risk of disease progression; 3) Patients who have been diagnosed with MS should start treatment with fundamental DMTs unless the disease course has been highly active; 4) MAGNIMS score may be a suitable and simplified assessment tool for measuring treatment response to DMTs; 5) Patients treated with corticosteroids and NSIS should be switched to the standardized DMT treatment during remission in accordance with disease activity.

Narrative Review on the Use of Cladribine Tablets as Exit Therapy for Stable Elderly Patients with Multiple Sclerosis.

The number of ageing people with relapsing multiple sclerosis (RMS) is increasing. The efficacy of disease-modifying therapies (DMTs) for RMS declines with age. Also, older persons with MS may be more susceptible to infections, hospitalisations and malignancy. Aging people with MS have higher rates of comorbidities versus aged-matched controls, increasing the individual risk of disability. We review the therapeutic properties of cladribine tablets (CladT) in ageing people with RMS, with regard to their utility for allowing these individuals to cease continuous administration of a DMT (i.e. to act as an "exit therapy"). CladT is thought to be an immune reconstitution therapy, in that two short courses of oral treatment 1 year apart provide suppression of MS disease activity in responders that far outlasts the duration of treatment and post-treatment reductions in lymphocyte counts. Post hoc analyses, long-term follow-up of populations with RMS in randomised trials, and real-world evidence suggest that the efficacy of CladT is probably independent of age, although more data in the elderly are still needed. No clear adverse signals for lymphopenia or other adverse safety signals have emerged with increasing age, although immunosenescence in the setting of age-related "inflammaging" may predispose elderly patients to a higher risk of infections. Updating vaccination status is recommended, especially against pneumococci and herpes zoster for older patients, to minimise the risk of these infections. CladT may be a useful alternative treatment for ageing people with MS who often bear a burden of multiple comorbidities and polypharmacy and who are more exposed to the adverse effects of continuous immunosuppressive therapy.

Radiologically isolated syndrome in the spectrum of multiple sclerosis.

The radiologically isolated syndrome (RIS) currently represents the earliest detectable preclinical phase of multiple sclerosis (MS). Remarkable advancements have been recently made, including the identification of risk factors for disease evolution, revisions to the existing 2009 RIS criteria, and our understanding of the impact of early disease-modifying therapy use in the prevention/delay of symptomatic MS from two randomized clinical trials. Here, we discuss RIS in the context of the spectrum of MS, implications in the clinical management of individuals, and provide insights into future opportunities and challenges given the anticipated inclusion of asymptomatic MS in the formal definition of MS.

Experimental Animal Models of Prodromal Parkinson's Disease.

There is an estimated 35-45% loss of striatal dopamine at the time of diagnosis of Parkinson's disease (PD), and cases clinically diagnosed in the early stages may already be pathologically in advanced stages. Recent large-scale clinical trials of disease-modifying therapies (DMT) also suggest the necessity of targeting patients at earlier stages of the disease. From this perspective, the prodromal phase of PD is currently the focus of attention, emphasizing the need for a prodromal mouse model that accurately reflects the pathophysiology, along with early biomarkers. To establish prodromal animal model of PD with high face validity that reflects the disease state, the model must possess high construct validity that accurately incorporates clinical and pathological features in the prodromal phase. Furthermore, as a preclinical model of DMT, the model must possess high predictive validity to accurately evaluate the response to intervention. This review provides an overview of animal models which reflect the characteristics of prodromal PD, including alpha-synuclein (aS) accumulation and associated early non-motor symptoms, with a focus on the aS propagation model and genetic model. In addition, we discuss the challenges associated with these models. The genetic model often fails to induce motor symptoms, while aS propagation models skip the crucial step of initial aS aggregate formation, thereby not fully replicating the entire natural course of the disease. Identifying factors that induce the transition from prodromal to symptomatic phase is important as a preclinical model for DMT to prevent or delay the onset of the disease.

Disparities in DMT treatment: Demographic and neurocognitive differences between MS patients currently treated versus not treated with disease-modifying therapies.

BACKGROUND: Current treatment guidelines recommend consideration of disease-modifying therapy (DMT) for all multiple sclerosis (MS) patients, but barriers to access have begun to be identified. In particular, prior studies have found that people with higher education have better access to DMTs, perhaps explained by the association of higher education with higher income. And while the majority of people with MS are women, being male is also associated with higher income. These factors argue for the need to better understand whether there are differences in DMT uptake based on sex and education. Finally, in addition to well-documented benefits of DMTs for slowing disease progression, there is growing evidence to suggest benefits of DMTs for cognitive functioning. OBJECTIVE: Determine whether rates of DMT treatment differ based on education and sex. Secondarily, we investigate whether neurocognitive test performance differs in treated versus not treated groups. METHODS: In cross-sectional data, mixed effects linear regression evaluated differences in education and sex of those treated versus not treated with DMTs. Models included the following predictors: age, disease duration, MS subtype, sex/education, disability, atrophy, and T2 lesion volume. Propensity score weights were extracted to obtain unbiased estimates of the relationship between DMT status and each outcome of interest. The same models evaluated performance differences between groups on an iPad-based processing speed test (PST) and manual dexterity test (MDT). RESULTS: Controlling for covariates, individuals with less education (OR=1.09, 95 % CI=[1.03, 1.14], p = 0.003) and women (OR=0.80, 95 % CI=[0.72, 0.90], p < 0.001) were less likely to be currently treated with DMTs. Small effect size association was shown for DMT treatment with better performance on PST (beta=0.09, CI=[0.06, 0.13], p < 0.001) and MDT (beta=0.05, CI=[0.01,0.08], p = 0.011). CONCLUSIONS: Women and people with lower education had a lower likelihood of being currently treated with DMTs. After controlling for all relevant variables, an independent (small) association of DMT treatment to better performance on tests of processing speed and fine motor dexterity was found. Reasons for disparities remain to be investigated in future work, and may include employment status, health insurance coverage, or sex differences in risk tolerance.

Expert opinion on the use of contraception in people with multiple sclerosis.

BACKGROUND: Current guidance on the selection of appropriate contraception for people with multiple sclerosis (PwMS) is lacking. OBJECTIVE: To address this gap, an expert-led consensus program developed recommendations to support clinicians in discussing family planning and contraception with women and men with multiple sclerosis (MS). METHODS: A multidisciplinary steering committee (SC) of 13 international clinical experts led the program, supported by an extended faculty of 32 experts representing 18 countries. A modified Delphi methodology was used for decision-making and consensus-building. The SC drafted 15 clinical questions focused on patient-centered care, selection of contraception, and timing of stopping/starting contraception and disease-modifying therapies (DMTs). Statements addressing each question were drafted based on evaluation of published evidence and the experts' clinical experience. Consensus was reached if ⩾75% of respondents agreed (scoring 7-9 on a 9-point scale) with each recommendation. RESULTS: Consensus was reached on 24 of 25 proposed recommendations, including how and when to discuss contraception, types and safety of contraceptives, and how to evaluate the most appropriate contraceptive options for specific patient groups, including those with significant disability or being treated with DMTs. CONCLUSION: These expert recommendations provide the first practical, relevant, and comprehensive guidance for clinicians on the selection of contraception in PwMS.

Role of Teplizumab, a Humanized Anti-CD3 Monoclonal Antibody, in Managing Newly Diagnosed Type 1 Diabetes: An Updated Systematic Review and Meta-Analysis.

OBJECTIVE: Teplizumab has emerged as a potential disease-modifying drug in type 1 diabetes (T1D). This meta-analysis sought to summarize the therapeutic effect of teplizumab in newly diagnosed patients with T1D. METHODS: Randomized controlled trials involving patients with T1D receiving teplizumab in the intervention arm and placebo (or no active intervention) in the control arm were searched throughout the electronic databases. The primary outcome was the change in area under the curve of C-peptide levels from baseline. RESULTS: Seven reports from 6 studies involving 834 subjects met the inclusion criteria. Compared to teplizumab, greater reductions in area under the curve of C-peptide from the baseline values were observed in the control group after 6 months (mean difference [MD] 0.07 nmol/L [0.01, 0.13], P = .02), after 12 months (MD 0.07 nmol/L [0.04, 0.11], P = .0001), after 18 months (MD 0.10 nmol/L [0.06, 0.14], P < .00001), and after 24 months (MD 0.07 nmol/L [0.01, 0.14], P = .03) of interventions. Moreover, fewer patients treated with teplizumab had a decreased C-peptide response after 6 months (odds ratio [OR] 0.21), after 12 months (OR 0.17), after 18 months (OR 0.30), and after 24 months (OR 0.12) of treatment. The preservation of endogenous insulin production was supported by reduced use of exogenous insulin with maintenance of comparable glycemic control for up to 18 months post-treatment. Teplizumab imparted higher risks of grade 3 or higher adverse events, adverse events leading to study medication discontinuation, nausea, rash, and lymphopenia. CONCLUSION: The results of the meta-analysis support teplizumab as a promising disease-modifying therapy for newly diagnosed T1D.

Natural polyphenol: Their pathogenesis-targeting therapeutic potential in Alzheimer's disease.

Alzheimer's disease (AD) is a detrimental neurodegenerative disease affecting the elderly. Clinically, it is characterized by progressive memory decline and subsequent loss of broader cognitive functions. Current drugs provide only symptomatic relief but do not have profound disease-modifying effects. There is an unmet need to identify novel pharmacological agents for AD therapy. Neuropathologically, the characteristic hallmarks of the disease are extracellular senile plaques containing amyloid ß-peptides and intracellular neurofibrillary tangles containing hyperphosphorylated microtubule-associated protein tau. Simultaneously, oxidative stress, neuroinflammation and mitochondrial dysfunction in specific brain regions are early events during the process of AD pathologic changes and are associated with Aß/tau toxicity. Here, we first summarized probable pathogenic mechanisms leading to neurodegeneration and hopefully identify pathways that serve as specific targets to improve therapy for AD. We then reviewed the mechanisms that underlie disease-modifying effects of natural polyphenols, with a focus on nuclear factor erythroid 2-related factor 2 activators for AD treatment. Lastly, we discussed challenges in the preclinical to clinical translation of natural polyphenols. In conclusion, there is evidence that natural polyphenols can be therapeutically useful in AD through their multifaceted mechanism of action. However, more clinical studies are needed to confirm these effects.

Multi-actor system dynamics in access to disease-modifying treatments for multiple sclerosis in Southeast Asia: A regional survey and suggestions for improvement.

BACKGROUND: Despite the global availability of multiple sclerosis (MS) treatments, accessing and financing them in Southeast Asia (SEA) remains a challenge. This descriptive survey-based study aimed to describe the current state of MS treatment access and local access dynamics within this region. METHODS: The survey questionnaire, comprising of 15 closed-ended and five open-ended questions, was developed by three neurologists with expertise in MS and routine MS patient management, or had training in neuroimmunology. Questionnaire development was guided by the recent Atlas of MS and in alignment with the Access to Treatment framework, focusing on MS diagnosis and treatment issues in SEA. Fifteen neurologists experienced in managing MS across the region were identified as key informants for this study. RESULTS: All fifteen neurologists participated in the survey via email and videoconferencing between January 2020 and February 2023, which included the following countries: Brunei, Cambodia, Indonesia, Malaysia, Myanmar, Lao PDR, Philippines, Singapore, Thailand, Timor-Leste, and Vietnam. All had at least five years of experience in managing MS patients and six had previously completed a neuroimmunology fellowship programme. SEA countries showed disparities in healthcare financing, availability of neurologists, MS treatments, and investigative tools. Access to MS disease-modifying treatments (DMTs) is hindered by high cost, lack of MS specialists, and weak advocacy efforts. On-label DMTs are not listed as essential medicines regionally except for interferon beta1a and teriflunomide in Malaysia. On-label monoclonals are available only in Malaysia, Singapore, and Thailand. Generic on-label DMTs are unavailable due to lack of distributorship and expertise in using them. Off-label DMTs (azathioprine, methotrexate, and rituximab) predominate in most SEA countries. Other challenges include limited access to investigations, education, and knowledge about DMTs among general neurologists, and absence of registries and MS societies. Patient champions, communities, and MS organisations have limited influence on local governments and pharmaceutical companies. Despite its increasing prevalence, there is a lack of concerted priority setting due to MS being perceived as a rare, non-communicable disease. CONCLUSION: This study highlights the distinct dynamics, challenges, and research gaps within this region, and provides suggestions to improve MS diagnosis, education, and medicine access.

Persons with multiple sclerosis older than 55 years: an analysis from the German MS registry.

BACKGROUND: Persons with MS (PwMS) ≥ 55 years are underrepresented in therapy studies leading to a lack of evidence. OBJECTIVE AND METHODS: To study the subgroup of PwMS ≥ 55 years in the German MS registry in comparison with PwMS < 55 years. Endpoints of interest were the grade of disability, leading symptoms, clinical and magnetic resonance imaging activity, and use of disease modifying therapy. RESULTS: At the time of analysis, data from 40,428 PwMS were available for analysis. In PwMS aged ≥ 65 and PwMS aged ≥ 55 to 64 years, compared with PwMS aged < 55 years, the mean Expanded Disability Status Scale Scores were higher (5.3, 4.2 and 2.7, respectively), while the proportion of individuals with current use of disease modifying therapy was lower (42.6%, 60.9% and 76.7%, respectively). The older patient groups were more likely to be labeled with progressive MS and the frequency of occupational invalidity was high (38.8% in PwMS aged ≥ 55 to 64 years). Gait disorder, fatigue, bladder dysfunction, and spasticity were among the leading symptoms in PwMS aged ≥ 55 years. CONCLUSION: PwMS ≥ 55 years have a high degree of disability, but a large proportion do not receive disease modifying therapy, exposing an unmet need.

Treatment access and satisfaction on disease-modifying therapies of neuromyelitis optica spectrum disorder patients in China: a cross-sectional survey.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a rare and debilitating disease that has become more widely recognized in China. Legislative measures have been implemented by the government to improve treatment access for rare diseases. Objectives: To investigate the diagnostic journey, treatment status, treatment accessibility, and treatment satisfaction of the NMOSD patients on disease-modifying therapies (DMTs) in China. Design: A patient online survey. Methods: This cross-sectional online survey was conducted between November 2022 and January 2023. Patients over 18 years old and diagnosed with NMOSD were included. The questionnaire consisted of five sections covering demographics, diagnostic and treatment experiences, DMTs availability, cost and affordability, and treatment satisfaction using the Treatment Satisfaction Questionnaire for Medication (version II). Patient opinions and demands were also collected at the end of the survey. Results: A total of 375 patients diagnosed with NMOSD were recruited, of which 321 patients used DMTs. It required 1.22 ± 3.22 years and 3.58 ± 4.24 hospital visits for a definitive diagnosis. One-third of the patients still needed to travel for over 2 h to access DMTs. The total treatment expenditure was estimated to be CNY 59,827.00 (USD 8315.95) a year. Drug expenses alone accounted for 52.22% of the average annual household income. The most common challenges perceived were the inability to afford treatment and a lack of effective options. No significant difference was found in treatment satisfaction among DMTs, except that rituximab scored lowest in convenience compared to other DMTs. Patients' age and travel time required to obtain medications were negatively associated with global treatment satisfaction. Conclusion: In China, patients with NMOSD face challenges in obtaining proper treatment due to diagnostic difficulties, distant medication access, and high costs. Policies should prioritize improving disease education and alleviating financial burdens for the patients.

Disease-modifying therapy in progressive multiple sclerosis: a systematic review and network meta-analysis of randomized controlled trials.

Background: Currently, disease-modifying therapies (DMTs) for progressive multiple sclerosis (PMS) are widely used in clinical practice. At the same time, there are a variety of drug options for DMTs, but the effect of the drugs that can better relieve symptoms and improve the prognosis are still inconclusive. Objectives: This systematic review aimed to evaluate the efficacy and safety of DMTs for PMS and to identify the best among these drugs. Methods: MEDLINE, EMBASE, the Cochrane Library, and clinicaltrials.gov were systematically searched to identify relevant studies published before 30 January, 2023. We assessed the certainty of the evidence using the confidence in the network meta-analysis (CINeMA) framework. We estimated the summary risk ratio (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes with 95% credible intervals (CrIs). Results: We included 18 randomized controlled trials (RCTs) involving 9,234 patients in the study. DMT can effectively control the disease progression of MS. Among them, mitoxantrone, siponimod, and ocrelizumab are superior to other drug options in delaying disease progression (high certainty). Mitoxantrone was the best (with high certainty) for mitigating deterioration (progression of disability). Ocrelizumab performed best on the pre- and post-treatment Timed 25-Foot Walk test (T25FW; low certainty), as did all other agents (RR range: 1.12-1.05). In the 9-Hole Peg Test (9HPT), natalizumab performed the best (high certainty), as did all other agents (RR range: 1.59-1.09). In terms of imaging, IFN-beta-1b performed better on the new T2 hypointense lesion on contrast, before and after treatment (high certainty), while siponimod performed best on the change from baseline in the total volume of lesions on T2-weighted image contrast before and after treatment (high certainty), and sWASO had the highest area under the curve (SUCRA) value (100%). In terms of adverse events (AEs), rituximab (RR 1.01), and laquinimod (RR 1.02) were more effective than the placebo (high certainty). In terms of serious adverse events (SAEs), natalizumab (RR 1.09), and ocrelizumab (RR 1.07) were safer than placebo (high certainty). Conclusion: DMTs can effectively control disease progression and reduce disease deterioration during the treatment of PMS. Systematic review registration: https://inplasy.com/?s=202320071, identifier: 202320071.

Disease-modifying therapy initiation patterns in multiple sclerosis in three large MS populations.

Background: Treatment guidelines recommend early disease-modifying therapy (DMT) initiation after diagnosis of multiple sclerosis (MS). Multinational comparative studies that assess time to DMT initiation in MS may allow detection of barriers inherent to healthcare systems to explain potential adverse systematic delays in commencing DMTs. Objectives: To investigate and compare the time to first DMT and its association with sociodemographic and clinical variables after MS diagnosis in three large MS registries. Design: This observational study was conducted using data from the German MS Registry (GMSR), the North American Research Committee on MS Registry (NARCOMS, US data only), and the United Kingdom MS Registry (UKMSR, both self- and clinician-reported). Methods: Data from relapsing people with MS (PwMS), with a diagnosis of MS between 2014 and 2019, and available DMT and disability status were pooled using a meta-analytic approach. Results: A total of 5395 PwMS were included in the analysis (GMSR: n = 2658; NARCOMS: n = 447; UKMSR: n = 2290). Kaplan-Meier estimates for the time to first DMT [median months (95% CI)] were 2.0 (1.9-2.0), 3.0 (2-4), and 9.0 (7.7-10.6) for GMSR, NARCOMS, and UKMSR, respectively. Pooled multivariable Cox regression demonstrated shorter time to first DMT for PwMS diagnosed after 2017 [1.65 (1.42-1.92), p < 0.01], and longer time to DMT when a higher-efficacy DMT was selected (0.69 (0.54-0.90), p < 0.0001]. Conclusion: Time to DMT initiation differs across the populations studied, indicating that barriers may exist in early access to DMT, particularly in the United Kingdom. However, a consistent decrease in time to DMT initiation was noted since 2017 across all registries. Further studies are warranted comparing the effects of time to DMT and time to higher-efficacy DMT on long-term outcome.

Holistic, Long-Term Management of People with Relapsing Multiple Sclerosis with Cladribine Tablets: Expert Opinion from France.

Cladribine tablets (CladT) has been available for therapeutic use in France since March 2021 for the management of highly active relapsing multiple sclerosis (RMS). This high-efficacy disease-modifying therapy (DMT) acts as an immune reconstitution therapy. In contrast to most high-efficacy DMTs, which act via continuous immunosuppression, two short courses of oral treatment with CladT at the beginning of years 1 and 2 of treatment provide long-term control of MS disease activity in responders to treatment, without the need for any further pharmacological treatment for several years. Although the labelling for CladT does not provide guidance beyond the initial treatment courses, real-world data on the therapeutic use of CladT from registries of previous clinical trial participants and patients treated in routine practice indicate that MS disease activity is controlled for a period of years beyond this time for a substantial proportion of patients. Moreover, this clinical experience has provided useful information on how to initiate and manage treatment with CladT. In this article we, a group of expert neurologists from France, provide recommendations on the initiation of CladT in DMT-naïve patients, how to switch from existing DMTs to CladT for patients with continuing MS disease activity, how to manage patients during the first 2 years of treatment and finally, how to manage patients with or without MS disease activity in years 3, 4 and beyond after initiating treatment with CladT. We believe that optimisation of the use of CladT beyond its initial courses of treatment will maximise the benefits of this treatment, especially early in the course of MS when suppression of focal inflammation in the CNS is a clinical priority to limit MS disease progression.

Substantial and comparable suppression of disease activity following early initiation of cladribine tablets, ocrelizumab or alemtuzumab as first pharmacologic treatment for relapsing multiple sclerosis: A real world study.

BACKGROUND: We describe the efficacy and safety of recent high efficacy disease DMTs in DMT-naive patients with highly active RMS. METHODS: This was a retrospective, cross sectional study from the Kuwait national MS registry. Patients with RMS who received alemtuzumab, cladribine tablets or ocrelizumab as their first DMT for RMS, with ≥2 year of follow up were included. The primary endpoint was the change in relapse rate from treatment initiation to 1 year; changes in disability (Expanded Disability Status Scale [EDSS]), radiologic activity, the proportion with no evidence of disease activity-3 (NEDA-3), and the frequency of adverse events were secondary endpoints. RESULTS: Among 123 RRMS patients, 59 received ocrelizumab, 32 received cladribine tablets and 32 received alemtuzumab. About two-thirds (65%) were women. Substantial and similar (p>0.05) reductions occurred at the end of follow-up in annual relapse rate (by 93.2% for ocrelizumab, 87.5% for cladribine tablets, and 90.6% for alemtuzumab). The proportion with new T2 of gadolinium-enhancing MRI lesions across the three groups was reduced from 85-100% to 7-13%. Rates of confirmed disability progression were low (ocrelizumab 6.9%, cladribine tablets 3.1%, alemtuzumab 0%; p=0.280); disability was reduced in 15%, 22% and 38%, respectively. NEDA-3 was observed in 89.8%, 87.5%, and 84.4, respectively (p=0.784). No new or unexpected safety issues occurred. CONCLUSION: Ocrelizumab, cladribine tablets and alemtuzumab reduced relapse rates and MRI activity, and prevented disease progression, when are initiated early in DMT-naive RMS patients. These data support the early use of high-efficacy DMTs for people with highly active RMS.

Documento de consenso de la Sociedad Española de Neurología sobre el tratamiento de la esclerosis múltiple y manejo holístico del paciente 2023 / Consensus statement of the Spanish Society of Neurology on the treatment of multiple sclerosis and holistic patient management in 2023

El último documento de consenso del Grupo de Estudio de Enfermedades Desmielinizantes de la Sociedad Española de Neurología sobre el tratamiento de la esclerosis múltiple (EM) data del año 2016. Aunque muchas consideraciones continúan todavía vigentes, desde entonces se han producido cambios significativos en el manejo y tratamiento de esta enfermedad, motivados no solo por la aprobación de nuevos fármacos con diferentes mecanismos de acción, sino también por la evolución de conceptos otrora consolidados. Esto ha permitido abordar situaciones especiales como el embarazo y la vacunación desde otra perspectiva, e incluir nuevas variables en la toma de decisiones en práctica clínica, como plantear tratamiento modificador de la enfermedad (TME) de alta eficacia en fases tempranas, considerar la perspectiva del paciente y utilizar nuevas tecnologías como monitorización remota. Estos cambios han motivado la presente actualización del consenso mediante metodología Delphi, con el objetivo de reflejar el nuevo paradigma de manejo del paciente con EM basándose en la evidencia científica y la experiencia clínica de los participantes. Entre las principales conclusiones destacan como recomendaciones: iniciar TME inmunomodulador en el síndrome radiológico aislado con actividad radiológica persistente, evaluar la perspectiva del paciente y abandonar la terminología «líneas de tratamiento» en la clasificación de los TME (consenso mayor del 90%). Tras el diagnóstico de EM la elección del primer TME debería considerar la presencia/ausencia de factores de mal pronóstico (epidemiológicos, clínicos, radiológicos y biomarcadores) para la aparición de nuevos brotes o progresión de discapacidad, pudiendo plantear desde el inicio TME de alta eficacia. (AU)

The last consensus statement of the Spanish Society of Neurology's Demyelinating Diseases Study Group on the treatment of multiple sclerosis (MS) was issued in 2016. Although many of the positions taken remain valid, there have been significant changes in the management and treatment of MS, both due to the approval of new drugs with different action mechanisms and due to the evolution of previously fixed concepts. This has enabled new approaches to specific situations such as pregnancy and vaccination, and the inclusion of new variables in clinical decision-making, such as the early use of high-efficacy disease-modifying therapies (DMT), consideration of the patient's perspective, and the use of such novel technologies as remote monitoring. In the light of these changes, this updated consensus statement, developed according to the Delphi method, seeks to reflect the new paradigm in the management of patients with MS, based on the available scientific evidence and the clinical expertise of the participants. The most significant recommendations are that immunomodulatory DMT be started in patients with radiologically isolated syndrome with persistent radiological activity, that patient perspectives be considered, and that the term “lines of therapy” no longer be used in the classification of DMTs (> 90% consensus). Following diagnosis of MS, the first DMT should be selected according to the presence/absence of factors of poor prognosis (whether epidemiological, clinical, radiological, or biomarkers) for the occurrence of new relapses or progression of disability; high-efficacy DMTs may be considered from disease onset. (AU)