Introducing a core dataset for real-world data in multiple sclerosis registries and cohorts: Recommendations from a global task force.

BACKGROUND: As of September 2022, there was no globally recommended set of core data elements for use in multiple sclerosis (MS) healthcare and research. As a result, data harmonisation across observational data sources and scientific collaboration is limited. OBJECTIVES: To define and agree upon a core dataset for real-world data (RWD) in MS from observational registries and cohorts. METHODS: A three-phase process approach was conducted combining a landscaping exercise with dedicated discussions within a global multi-stakeholder task force consisting of 20 experts in the field of MS and its RWD to define the Core Dataset. RESULTS: A core dataset for MS consisting of 44 variables in eight categories was translated into a data dictionary that has been published and disseminated for emerging and existing registries and cohorts to use. Categories include variables on demographics and comorbidities (patient-specific data), disease history, disease status, relapses, magnetic resonance imaging (MRI) and treatment data (disease-specific data). CONCLUSION: The MS Data Alliance Core Dataset guides emerging registries in their dataset definitions and speeds up and supports harmonisation across registries and initiatives. The straight-forward, time-efficient process using a dedicated global multi-stakeholder task force has proven to be effective to define a concise core dataset.

Epilepsy as a predictor of disease progression in multiple sclerosis.

BACKGROUND: Epilepsy development during the course of multiple sclerosis (MS) is considered to be the result of cortical pathology. However, no long-term data exist on whether epilepsy in MS also leads to increasing disability over time. OBJECTIVE: To examine if epilepsy leads to more rapid disease progression. METHODS: We analyzed the data of 31,052 patients on the German Multiple Sclerosis Register in a case-control study. RESULTS: Secondary progressive disease course (odds ratio (OR) = 2.23), age (OR = 1.12 per 10 years), and disability (OR = 1.29 per Expanded Disability Status Scale (EDSS) point) were associated with the 5-year prevalence of epilepsy. Patients who developed epilepsy during the course of the disease had a higher EDSS score at disease onset compared to matched control patients (EDSS 2.0 vs 1.5), progressed faster in each dimension, and consequently showed higher disability (EDSS 4.4 vs 3.4) and lower employment status (40% vs 65%) at final follow-up. After 15 years of MS, 64% of patients without compared to 54% of patients with epilepsy were not severely limited in walking distance. CONCLUSION: This work highlights the association of epilepsy on disability progression in MS, and the need for additional data to further clarify the underlying mechanisms.

Time to diagnosis in multiple sclerosis: Epidemiological data from the German Multiple Sclerosis Registry.

OBJECTIVE: To investigate the time to diagnosis in multiple sclerosis (MS) in Germany. METHODS: Analysis of real-world registry data from the German Multiple Sclerosis Registry (GMSR) and performing a primary analysis in patients where month-specific registration of the dates of onset and diagnosis was available. RESULTS: As of January 2020, data of a total of 28,658 patients with MS were extracted from the GMSR, with 9836 patients included in the primary analysis. The mean time to diagnosis was shorter following the introduction of the first magnetic resonance imaging (MRI)-based McDonald criteria in 2001. This effect was most pronounced in younger adults below the age of 40 years with relapsing onset multiple sclerosis (ROMS), with a decrease from 1.9 years in 2010 to 0.9 years in 2020, while unchanged in patients aged 40-50 years (1.4 years in 2010 and 1.3 years in 2020). In the limited number of paediatric onset MS patients, the time to diagnosis was longer and did not change (2.9 years). CONCLUSION: The current sensitive MRI-based diagnostic criteria have likely contributed to an earlier diagnosis of MS in Germany in younger adults aged 18-39 years with ROMS. Whether this translated to earlier initiation of disease-modifying treatment or had a beneficial effect on patient outcomes remains to be demonstrated.

Effect of applying inclusion and exclusion criteria of phase III clinical trials to multiple sclerosis patients in routine clinical care.

BACKGROUND: Newly approved, drug-modifying therapies are associated with still unknown adverse events, although clinical trials leading to approval have strict inclusion and exclusion criteria and analyse safety and efficacy. OBJECTIVES: The aim of this study was to analyse the eligibility of multiple sclerosis (MS) patients treated in routine care into the phase III clinical trial of the respective drug. METHODS: In total, 3577 MS patients with 4312 therapies were analysed. Patients with primary-progressive MS were excluded. Inclusion and exclusion criteria of phase III clinical trials in relapsing-remitting MS were adopted and subsequently applied. A comparison in clinical and sociodemographic characteristics was made between patient who met the criteria and those who did not. RESULTS: 83% of registered patients would not have been eligible to the respective phase III clinical trial. Relapse was the single most frequent criterion not fulfilled (74.7%), followed by medication history (21.2%). CONCLUSION: The majority of MS patients treated in routine care would not have met clinical trials criteria. Thus, the efficacy and safety of therapies in clinical trials can differ from those in the real world. Broader phase III inclusion criteria would increase their eligibility and contribute to a better generalizability of the results in clinical trials.

Prevalence of pediatric multiple sclerosis in Germany: A nationwide population-based analysis.

BACKGROUND AND PURPOSE: Prevalence data are needed to reveal trends regarding the pediatric multiple sclerosis (MS) situation worldwide. The aim was to identify changes in MS diagnosis prevalence in pediatric patients over a 10-year period in Germany. METHODS: This analysis is based on nationwide outpatient claims data of children aged <18 years covered by the German statutory health insurance (n = 11,381,939 in 2018). People with MS (PwMS) had ≥1 documented MS diagnosis (International Classification of Diseases, 10th Revision, German modification code G35.x). The annual pediatric MS diagnosis prevalence was analyzed regarding age, sex, and place of residence during 2009-2018. RESULTS: The prevalence of pediatric MS developed from 5.3 (2009) to 5.4 (2018)/100,000 insured population aged <18 years. The MS prevalence in patients aged 15-17 years showed a moderate increase over 10 years (19.6-22.7/100,000), whereas patients ≤14 years old showed a slight decrease (1.9-1.7/100,000). The sex ratio (female:male) in 2018 was relatively balanced in PwMS aged ≤14 years (1.32) but female-dominated in those aged 15-17 years (2.47). The formerly different prevalence of pediatric MS between East and West Germany has converged since 2012. CONCLUSIONS: So far, this is the largest study of pediatric MS prevalence in terms of source population size (87% of German children <18 years of age, n = 11,381,939 in 2018) and study period (2009-2018) worldwide. The analyses revealed an increase in MS prevalence and a female-dominated sex ratio in "older" adolescents compared to younger patients.

COVID-19 in people with multiple sclerosis: A global data sharing initiative.

BACKGROUND: We need high-quality data to assess the determinants for COVID-19 severity in people with MS (PwMS). Several studies have recently emerged but there is great benefit in aligning data collection efforts at a global scale. OBJECTIVES: Our mission is to scale-up COVID-19 data collection efforts and provide the MS community with data-driven insights as soon as possible. METHODS: Numerous stakeholders were brought together. Small dedicated interdisciplinary task forces were created to speed-up the formulation of the study design and work plan. First step was to agree upon a COVID-19 MS core data set. Second, we worked on providing a user-friendly and rapid pipeline to share COVID-19 data at a global scale. RESULTS: The COVID-19 MS core data set was agreed within 48 hours. To date, 23 data collection partners are involved and the first data imports have been performed successfully. Data processing and analysis is an on-going process. CONCLUSIONS: We reached a consensus on a core data set and established data sharing processes with multiple partners to address an urgent need for information to guide clinical practice. First results show that partners are motivated to share data to attain the ultimate joint goal: better understand the effect of COVID-19 in PwMS.

Symptomatology and symptomatic treatment in multiple sclerosis: Results from a nationwide MS registry.

BACKGROUND: Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease. Over time, symptoms accumulate leading to increased disability of patients. OBJECTIVE: The objective of this article is to analyze the prevalence of symptoms and symptomatic treatment patterns in a nationwide MS registry. METHODS: Data sets from 35,755 patients were analyzed. RESULTS: More than two-thirds of patients were women with a mean age of 46.1 (±12.8) years. Median Expanded Disability Status Score (EDSS) was 3.0. The most frequently reported symptoms were fatigue, spasticity, and voiding disorders. In patients with short disease duration, fatigue was reported most frequently. Symptomatic treatment was most common for spasticity and depression, whereas fatigue was treated only in a third of affected patients. Almost a fifth of patients with EDSS ⩽ 3.5 and neuropsychological symptoms had retired from work. CONCLUSION: Whereas treatment for spasticity and depression is common in our cohort, sexual dysfunction, dysphagia, cognitive dysfunction, and fatigue are treated to a far lesser extent. The need for psychological support, physical, and occupational therapy has to be recognized as neuropsychological symptoms have a great impact on retirement at an early stage. Overall symptomatic treatment rates for the most common symptoms have increased over the last years (p < 0.001).

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.

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.

Subgroup analyses and patterns of multiple sclerosis health service utilisation: A cluster analysis.

Background: Previous investigations of multiple sclerosis (MS)-related healthcare have focused on utilisation of specific individual health services (e.g. hospital care, office-based neurologists) by people with MS (PwMS). Meanwhile, little is known about possible patterns of utilisation across health services and their potential differences across patient characteristics. Objective: To comprehensively analyse and identify patterns of MS-related health service utilisation and detect patient characteristics explaining such patterns. Methods: In 2021, we invited all PwMS insured by the largest insurance company in Lower Saxony, Germany, to take part in an online survey. We merged respondents' survey and health insurance claims data. We analysed MS-related health service utilisation and defined individual characteristics for subgroup analyses based on Andersen's Behavioural Model. We executed non-parametric missing value imputation and conducted hierarchical clustering to find patterns in health service utilisation. Results: Of 6928 PwMS, 1935 responded to our survey and 1803 were included in the cluster analysis. We identified four distinct health service utilisation clusters: (1) regular users (n = 1130), (2) assistive care users (n = 443), (3) low users (n = 195) and (4) special services users (n = 35). Clusters differ by patient characteristics (e.g. age, impairment). Conclusion: Our findings highlight the complexity of MS-related health service utilisation and provide relevant stakeholders with information allowing them to tailor healthcare planning according to utilisation patterns.

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.

Serum glial fibrillary acidic protein and disability progression in progressive multiple sclerosis.

OBJECTIVE: Progression prediction is a significant unmet need in people with progressive multiple sclerosis (pwPMS). Studies on glial fibrillary acidic protein (GFAP) have either been limited to single center with relapsing MS or were based solely on Expanded Disability Status Scale (EDSS), which limits its generalizability to state-of-the-art clinical settings and trials applying combined outcome parameters. METHODS: Serum GFAP and NfL (neurofilament light chain) were investigated in EmBioProMS participants with primary (PP) or secondary progressive MS. Six months confirmed disability progression (CDP) was defined using combined outcome parameters (EDSS, timed-25-foot walk test (T25FW), and nine-hole-peg-test (9HPT)). RESULTS: 243 subjects (135 PPMS, 108 SPMS, age 55.5, IQR [49.7-61.2], 135 female, median follow-up: 29.3 months [17.9-40.9]) were included. NfL (age-) and GFAP (age- and sex-) adjusted Z scores were higher in pwPMS compared to HC (p < 0.001 for both). 111 (32.8%) CDP events were diagnosed in participants with ≥3 visits (n = 169). GFAP Z score >3 was associated with higher risk for CDP in participants with low NfL Z score (i.e., ≤1.0) (HR: 2.38 [1.12-5.08], p = 0.025). In PPMS, GFAP Z score >3 was associated with higher risk for CDP (HR: 2.88 [1.21-6.84], p = 0.016). Risk was further increased in PPMS subjects with high GFAP when NfL is low (HR: 4.31 [1.53-12.13], p = 0.006). INTERPRETATION: Blood GFAP may help identify pwPPMS at risk of progression. Combination of high GFAP and low NfL levels could distinguish non-active pwPMS with particularly high progression risk.

Patient-reported outcome parameters and disability worsening in progressive multiple sclerosis.

OBJECTIVES: Detection and prediction of disability progression is a significant unmet need in people with progressive multiple sclerosis (PwPMS). Government and health agencies have deemed the use of patient-reported outcomes measurements (PROMs) in clinical practice and clinical trials a major strategic priority. Nevertheless, data documenting the clinical utility of PROMs in neurological diseases is scarce. This study evaluates if assessment of PROMs could track progression in PwPMS. METHODS: Emerging blood Biomarkers in Progressive Multiple Sclerosis (EmBioProMS) investigated PROMs (Beck depression inventory-II (BDI-II), multiple sclerosis impact scale-29 (MSIS-29), fatigue scale for motor and cognition (FSMC)) in PwPMS (primary [PPMS] and secondary progressive MS [SPMS]). PROMs were evaluated longitudinally and compared between participants with disability progression (at baseline; retrospective evidence of disability progression (EDP), and during follow up (FU); prospective evidence of confirmed disability progression (CDP)) and those without progression. In an independent cohort of placebo participants of the phase III ORATORIO trial in PPMS, the diagnostic and prognostic value of another PROMs score (36-Item Short Form Survey [SF-36]) regarding CDP was evaluated. RESULTS: EmBioProMS participants with EDP in the two years prior to inclusion (n = 136/227), or who suffered from CDP during FU (number of events= 88) had worse BDI-II, MSIS-29, and FSMC scores compared to PwPMS without progression. In addition, baseline MSIS29physical above 70th, 80th, and 90th percentiles predicted future CDP/ progression independent of relapse activity in EmBioProMS PPMS participants (HR of 3.7, 6.9, 6.7, p = 0.002, <0.001, and 0.001, respectively). In the placebo arm of ORATORIO (n = 137), the physical component score (PCS) of SF-36 worsened at week 120 compared to baseline, in cases who experienced progression over the preceding trial period (P = 0.018). Worse PCS at baseline was associated with higher hazard ratios of disability accumulation over the subsequent 120 weeks (HR: 2.01 [30th-], 2.11 [20th-], and 2.8 [10th percentile], P = 0.007, 0.012 and 0.005, respectively). CONCLUSIONS: PROMs could provide additional, practical, cost-efficient, and remotely accessible insight about disability progression in PMS through standardized, structured, and quantifiable patient feedback.

Application of Statistical Methods for Central Statistical Monitoring and Implementations on the German Multiple Sclerosis Registry.

Monitoring of clinical trials is a fundamental process required by regulatory agencies. It assures the compliance of a center to the required regulations and the trial protocol. Traditionally, monitoring teams relied on extensive on-site visits and source data verification. However, this is costly, and the outcome is limited. Thus, central statistical monitoring (CSM) is an additional approach recently embraced by the International Council for Harmonisation (ICH) to detect problematic or erroneous data by using visualizations and statistical control measures. Existing implementations have been primarily focused on detecting inlier and outlier data. Other approaches include principal component analysis and distribution of the data. Here we focus on the utilization of comparisons of centers to the Grand mean for different model types and assumptions for common data types, such as binomial, ordinal, and continuous response variables. We implement the usage of multiple comparisons of single centers to the Grand mean of all centers. This approach is also available for various non-normal data types that are abundant in clinical trials. Further, using confidence intervals, an assessment of equivalence to the Grand mean can be applied. In a Monte Carlo simulation study, the applied statistical approaches have been investigated for their ability to control type I error and the assessment of their respective power for balanced and unbalanced designs which are common in registry data and clinical trials. Data from the German Multiple Sclerosis Registry (GMSR) including proportions of missing data, adverse events and disease severity scores were used to verify the results on Real-World-Data (RWD).

Epileptic seizures at multiple sclerosis onset and their role in disease progression.

Background: Epileptic seizures can occur throughout the course of multiple sclerosis (MS) and are associated with increasing disability progression over time. However, there are no data on whether epileptic seizures at the onset of MS also lead to increasing disability. Objective: To examine disease progression over time for MS patients with epileptic seizures at onset. Methods: We analyzed the data of 30,713 patients on the German Multiple Sclerosis Register in a case-control study for more than 15 years. MS patients with seizures at onset were further divided into subgroups with polysymptomatic and monosymptomatic onset to assess the impact of additional symptoms on disease progression. Results: A total of 46 patients had seizures as onset symptoms. Expanded Disability Status Scale (EDSS) within the first year was lower in the group with seizures at onset compared to controls (0.75 versus 1.6, p < 0.05), which changed until the last reported visit (3.11 versus 3.0). Both subgroups revealed increased EDSS progression over time compared to controls. Conclusion: Epileptic seizures at MS onset are associated with a higher amount of disability progression over time. Additional longitudinal data are needed to further clarify the impact of seizures on the pathophysiology of MS disease progression.

Frequency and Predictors of Relapses following SARS-CoV-2 Vaccination in Patients with Multiple Sclerosis: Interim Results from a Longitudinal Observational Study.

Despite protection from severe COVID-19 courses through vaccinations, some people with multiple sclerosis (PwMS) are vaccination-hesitant due to fear of post-vaccination side effects/increased disease activity. The aim was to reveal the frequency and predictors of post-SARS-CoV-2-vaccination relapses in PwMS. This prospective, observational study was conducted as a longitudinal Germany-wide online survey (baseline survey and two follow-ups). Inclusion criteria were age ≥18 years, MS diagnosis, and ≥1 SARS-CoV-2 vaccination. Patient-reported data included socio-demographics, MS-related data, and post-vaccination phenomena. Annualized relapse rates (ARRs) of the study cohort and reference cohorts from the German MS Registry were compared pre- and post-vaccination. Post-vaccination relapses were reported by 9.3% PwMS (247/2661). The study cohort's post-vaccination ARR was 0.189 (95% CI: 0.167-0.213). The ARR of a matched unvaccinated reference group from 2020 was 0.147 (0.129-0.167). Another reference cohort of vaccinated PwMS showed no indication of increased post-vaccination relapse activity (0.116; 0.088-0.151) compared to pre-vaccination (0.109; 0.084-0.138). Predictors of post-vaccination relapses (study cohort) were missing immunotherapy (OR = 2.09; 1.55-2.79; p < 0.001) and shorter time from the last pre-vaccination relapse to the first vaccination (OR = 0.87; 0.83-0.91; p < 0.001). Data on disease activity of the study cohort in the temporal context are expected for the third follow-up.

Occurrence and Risk Factors of Relapse Activity after Vaccination against COVID-19 in People with Multiple Sclerosis: 1-Year Follow-Up Results from a Nationwide Longitudinal Observational Study.

Several studies reported post-SARS-CoV-2-vaccination (PV) symptoms. Even people with multiple sclerosis (PwMS) have concerns about disease activity following the SARS-CoV-2 vaccination. We aimed to determine the proportion of PwMS with PV relapses, the PV annualized relapse rate (ARR), the time from vaccination to subsequent relapses, and identify sociodemographic/clinical risk factors for PV relapses. PwMS were surveyed several times at baseline and four follow-ups as part of a longitudinal observational study regarding the safety and tolerability of the SARS-CoV-2 vaccination. The inclusion criteria for this analysis were age ≥18 years, ≥1 SARS-CoV-2 vaccination, and ≥1-year observation period since initial vaccination. Of 2466 PwMS, 13.8% reported PV relapses (mostly after second [N = 147] or booster vaccination [N = 145]) at a median of 8.0 (first/third quantile: 3.55/18.1) weeks PV, with the shortest period following initial vaccination (3.95 weeks). The ARR was 0.153 (95% confidence interval: 0.138-0.168), with a median observation period since initial vaccination of 1.2 years. Risk factors for PV relapses were younger age, female gender, moderate-severe disability levels, concurrent autoimmune diseases, relapsing-remitting MS courses, no DMT, and relapses within the year prior to the first vaccination. Patients' health conditions before/during initial vaccination may play a more important role in PV relapse occurrence than vaccination per se.