Author Of 3 Presentations
PS05.02 - Validation of three Secondary Progressive Multiple Sclerosis classification methods in five registries within the SPMS Research Collaboration Network
Assigning Secondary Progressive Multiple Sclerosis (SPMS) course consistently is challenging as it is based on a gradual worsening in neurological disability independent of relapses. Clinical SPMS assignment may therefore vary between registries depending on clinical practice. Consequently, a comparison of SPMS between registries would benefit from an objective definition of SPMS.
To validate three different methods for classifying patients into Relapsing Remitting Multiple Sclerosis (RRMS) or SPMS, compared to the clinical assignment, in five European Multiple Sclerosis (MS) registries.
Data from MS registries in Czech Republic (11,336 patients), Denmark (10,255 patients), Germany (23,185 patients), Sweden (11,247 patients), and the United Kingdom (UK) (5,086 patients) were used. Patients with either RRMS or SPMS, age ≥ 18 years at index date (date with the latest Expanded Disability Status Scale (EDSS) observation) were included. Index period was 01/2017 - 12/2019. Three EDSS centric classification methods were applied; method 1: a modified real world EXPAND criteria (Kappos, L. et al., 2018. The Lancet 391(10127), 2018), method 2: the data-derived definition from Melbourne University but without pyramidal Functional Score (Lorscheider, J. et al., 2016. Brain 139(9)), method 3: the decision tree classifier from Karolinska Institutet (Ramanujam, R. et al., 2020. medRxiv, 2020.07.09.20149674). The classifications were compared to the clinical assignment, where sensitivity (SPMS as true positive), specificity (RRMS as true negative) and accuracy were calculated as similarity measurements.
The overall classification performance (sensitivity, specificity, accuracy) among classifiable patients were; method 1: (0.47, 0.85, 0.79), method 2: (0.77, 0.87, 0.85), method 3: (0.84, 0.83, 0.84). The proportions of unclassifiable patients with each method were; method 1: 20.0%, method 2: 32.2%, method 3: 0%. Methods 2 & 3 provided a high sensitivity, specificity and accuracy, while method 1 provided high specificity but low sensitivity. Method 3 was the only method having no unclassifiable patients.
Our findings suggest that these methods can be used to objectively assign SPMS with a fairly high performance in different registries. The method of choice depends on the research question and to what degree unclassifiable patients are tolerable.
PS05.04 - Ongoing disease modifying treatment associated with mis-classification of secondary progressive as relapsing-remitting multiple sclerosis
Until recently, disease modifying treatment options for MS patients with a secondary progressive course (SPMS) were limited, leading to the common practice of off-label treatment with drugs approved for relapsing-remitting MS. We previously showed that applying objective algorithms tend to increase the proportion of SPMS in MS registries, suggesting that SPMS is under-diagnosed in clinical practice, possibly related to available treatment options.
To compare characteristics of patients clinically assigned an RRMS course that are re-classified when an algorithm-based SPMS assignment method is applied.
Data from MS registries in the Czech Republic (11,336 patients), Denmark (10,255 patients), Germany (23,185 patients), Sweden (11,247 patients) and the United Kingdom (5,086 patients) were used. Inclusion criteria were patients with relapsing remitting (RR)MS or SPMS with age ≥ 18 years at the beginning of the study period (1 January 2017 – 31 December 2019). In addition to clinically assigned SPMS a data-driven assignment method was applied in the form of a decision tree classifier based on age and last EDSS (Ramanujam, R. et al., 2020. medRxiv, 2020.07.09.20149674).
Across the five registries 8,372 RRMS patients were re-assigned as SPMS (Denmark: n=1,566, Czech Republic: n=1,958, Germany: n=2,906, Sweden: n=648, United Kingdom: n=1,294) increasing the overall SPMS proportion from 17% to 31%. Re-assigned patients tended be younger, were older at onset and had experienced a quicker progression to SPMS. The overall proportion of clinically assigned SPMS patients on disease modifying treatments (DMTs) was 36% but varied greatly between registries (Czech Republic: 18%, Denmark: 35%, Germany: 50%, Sweden: 40%, and the United Kingdom: 12%) whereas a higher proportion of 69% (OR=4.0, P<0.00004) were on DMTs among RRMS patients re-assigned as SPMS (Czech Republic: 71%, Denmark: 68%, Germany: 78%, Sweden: 80%, and the United Kingdom 40%).
SPMS patients on DMTs may be clinically mis-classified as RRMS, most likely by not being re-assigned to SPMS after conversion has occurred. This challenges the use of time to SPMS conversion as an outcome in comparative effectiveness studies using real world evidence data and argues for the use of objective classification tools in the analysis of MS patient populations.
SS02.04 - First results of the COVID-19 in MS Global Data Sharing Initiative suggest anti-CD20 DMTs are associated with worse COVID-19 outcomes
- S. Simpson-Yap
- E. De Brouwer
- T. Kalincik
- N. Rijke
- J. Hillert
- C. Walton
- G. Edan
- Y. Moreau
- T. Spelman
- L. Geys
- T. Parciak
- C. Gautrais
- N. Lazovski
- A. Pirmani
- A. Ardeshirdavani
- L. Forsberg
- A. Glaser
- R. McBurney
- H. Schmidt
- A. Bergmann
- S. Braune
- A. Stahmann
- R. Middleton
- A. Salter
- A. Van Der Walt
- J. Rojas
- I. Van Der Mei
- R. Ivanov
- G. Sciascia Do Olival
- A. Dias
- M. Magyari
- D. Brum
- M. Mendes
- R. Alonso
- R. Nicholas
- J. Bauer
- A. Chertcoff
- A. Zabalza
- G. Arrambide
- G. Comi
- L. Peeters
As the COVID-19 pandemic amplifies, efforts to minimise the risk on vulnerable people are essential. People with multiple sclerosis (MS) may be a vulnerable group due to the high proportion taking long-term immunosuppressive disease-modifying therapies (DMTs). Studies from Italy and France suggest older age, higher disability and progressive MS are associated with severe COVID-19, yet there remains uncertainty around the influence of DMTs.
Given the many approved MS DMTs and the relatively low frequency of COVID-19 in MS patients per country, international data sharing is desirable to examine the impact of DMTs on COVID-19 severity. Here, we present the first results of the COVID-19 in MS global data sharing initiative of the MS International Federation and MS Data Alliance and many other data partners to inform MS clinical management during the COVID-19 pandemic.
Clinician-reported data from 21 countries were aggregated into a dataset of 1540 patients. Characteristics of admission to hospital, admission to intensive care unit (ICU), need for artificial ventilation, and death, were assessed in patients with confirmed or suspected COVID-19 infection using log-binomial regression. Adjusted prevalence ratios (aPR) were calculated adjusting for age, sex, MS type, and Expanded Disability Status Scale (EDSS).
Of 1540 patients, 476 (30.9%) with suspected and 776 (50.4%) with confirmed COVID-19 were included in the analysis. Older age, progressive MS and higher EDSS were associated with higher frequencies of severe outcomes. Anti-CD20 DMTs, ocrelizumab and rituximab, were positively associated with hospital admission (aPRs=1.19 & 1.58), ICU admission (aPRs=3.53 & 4.12), and the need for artificial ventilation (aPRs=3.17 & 7.27) compared to dimethyl fumarate. Higher frequencies of all three outcomes were associated with combined anti-CD20 DMT use compared to all other DMTs (hospitalisation aPR=1.49; ICU aPR=2.55; ventilation aPR=3.05) and compared to natalizumab (hospitalisation aPR=1.99; ICU aPR=2.39; ventilation aPR=2.84). Importantly, associations persisted on restriction to confirmed COVID-19 cases and upon exclusion of each contributing data source in turn. No associations were observed between DMTs and death.
This study used the largest federated international cohort of people with MS and COVID19 currently available. We demonstrate a consistent association of anti-CD20 DMTs with hospitalisation, ICU admission and use of artificial ventilation suggesting their use among MS patients at risk for COVID-19 exposure may be a risk factor for more severe COVID-19 disease. To address study limitations, further research incorporating comorbidities, smoking and body mass index is required. Alternative study designs are needed to address questions on COVID-19 susceptibility among people with MS.
Author Of 3 Presentations
P0315 - Disease modifying therapies in patients with aggressive MS (ID 1510)
There is a growing need to identify the course of aggressive multiple sclerosis (agMS) at an early stage so that affected patients can be treated with suitable disease modifying drugs (DMD). Investigations of treatment patterns in agMS and non-agMS patients are of interest, particularly in the context of the multitude of agMS definitions.
We aimed to determine characteristics of DMDs at baseline for comparative analyses of agMS patients and non-agMS patients.
We included patients from the German Multiple Sclerosis registry who started DMD use between 2010 and 2020 and were assessable on whether they are agMS patients according to a commonly used criterium of reaching EDSS ≥6.0, or by a criterium for highly active MS, i.e. ≥2 relapses during 12 months, or gd+ lesions on MRI. Both were assessed within the first 5 years of disease duration.
7249 patients fulfilled the inclusion criteria. Of these, 860 were identified as agMS. In agMS patients, Interferons (INFs) were the most frequently used DMDs with 34.8% followed by Glatiramer acetate (GLAT, 24.0%), Dimethyl fumarate (DMF, 15.8%), Teriflunomide (TRF, 7.6%), Natalizumab (NTZ, 5.4%), Fingolimod (FTY, 3.9%), Ocrelizumab (OCR, 3.2%), Steroids (STE, 1.8%), and others (3.5%). Regarding patients with non-agMS, INFs were also most frequent with 30.5% followed by GLAT (18.1%), DMF (13.2%), FTY (8.1%), NTZ (7.7%), TRF (7.5%), OCR (5.9%), STE (2.3%), and others (6.7%).
Within 5 years of disease duration, switches to another DMD were observed for 51% of agMS patients whereas only 17% of non-agMS switched to a second DMD. The average time spent on the first DMD was 1.3 (±1.1) years for agMS patients and 3.4 (±3.6) years for non-agMS patients (p<0.001; Mann-Whitney test). With regard to DMD use, significant differences between agMS and non-agMS patients were detected (p<0.001; χ2-test): INFs (p=0.009), GLAT (p<0.001) and DMF (p=0.03) were used significantly more often by agMS patients while FTY (p<0.001), NTZ (p=0.02) and OCR (p=0.002) were used more often by non-agMS patients.
Our analysis showed that in line with the (national) guidelines, the new immunomodulatory treatments are accessible to all MS patients. The patients classified as agMS spent less time on the first DMD than non-agMS patients did. To investigate causal factors in the connection between DMD preference and resulting disease progression, Marginal Structural Models are required, adjusting for relevant time-varying confounders such as patient demography, clinical visit details, MRI, and relapse parameters.
P0482 - Objective classification methods result in an increased proportion of secondary progressive multiple sclerosis in five patient registries (ID 1120)
Secondary progressive MS (SPMS) is a research area that is attracting more attention as better treatment options are still needed for this patient group. The assignment of SPMS by clinicians can differ between countries and may be influenced by drug prescription guidelines, reimbursement issues and other societal limitations.
To compare the clinically assigned SPMS proportion to three objective SPMS classification methods in five MS registries.
Data from MS registries in the Czech Republic (CR) (11,336 patients), Denmark (10,255 patients), Germany (23,185 patients), Sweden (11,247 patients) and the United Kingdom (UK) (5,086 patients) were used. Inclusion criteria were patients with relapsing remitting (RR)MS or SPMS with age ≥ 18 years at the beginning of the index period (1 January 2017 – 31 December 2019). In addition to clinically assigned SPMS three different classification methods were applied; method 1: modified real world EXPAND criteria (Kappos et al, Lancet 2018:391; 1263-1273), method 2: the data-derived definition from Melbourne University without the pyramidal Functional Systems Score (Lorscheider et al, Brain 2016:139; 2395-2405) and method 3: the decision tree classifier from Karolinska Institutet (Ramanujam, R. et al., 2020. medRxiv, 2020.07.09.20149674).
The SPMS proportions per registry, when comparing the clinically assigned SPMS with the results of the three classification methods, were CR: 8.8%, 21.3%, 22.1%, 25.0%; Denmark: 15.5%, 27.5%, 25.4%, 28.0%; Germany: 15.6%, 15.4%, 16.7%, 25.4%; Sweden: 23.7%, 20.8%, 23.2%, 24.6% and UK: 34.3%, 21.7%, 38.4%, 58.3% for clinical SPMS and methods 1, 2 and 3, respectively.
The proportion of clinically assigned SPMS patients varies between MS registries. When applying other classification methods, the SPMS proportion generally increases but remains variable between registries. As some of the classification methods have extensive requirements regarding data density, the number of unclassifiable samples created are considerable for some of the registries, which will influence the results. Providing a classification method that depends on objective information could prove useful when attempting to estimate the proportion of SPMS patients in MS populations but the choice of method may depend on the data characteristics of the individual MS registry.
P0847 - Characterization of relapsing multiple sclerosis patients treated with cladribine tablets in Germany since marketing authorization (ID 376)
In 2017, cladribine tablets (CT) were approved for highly active relapsing multiple sclerosis (RMS) in the European Union. Data on real-world utilization of this novel disease modifying drug (DMD) can inform evidence-based treatment selection.
To describe treatment and disease characteristics of RMS patients treated with CT in Germany since market authorization.
The German MS Registry (GMSR) captures data from more than 180 neurological centres. This study included all adult RMS patients newly treated with CT from August 2017 to September 18, 2019. We used descriptive statistics to summarize patient characteristics: age and sex, DMD history; and disease characteristics: relapse in the 12 months prior to CT initiation and Expanded Disability Status Scale (EDSS) score within the 90-days prior to or following CT initiation.
A total of 141 patients who initiated CT were identified across 46 neurological centers. The median (25 percentile, 75 percentile) age was 39 (32, 49) years with most patients being female (71%). The majority (91%) had a relapsing-remitting multiple sclerosis (RRMS) diagnosis at CT initiation, with a median disease duration of 9.5 (5.0, 16.3) years. Among persons (68.8%) with a documented EDSS score within 90-days of CT initiation, median EDSS was 2.5 (1.5, 4). 15% of persons were naïve to DMDs. Dimethyl fumarate (16%), daclizumab (16%), and fingolimod (13%) were the most common DMDs prior to CT initiation. In the 12 months prior to CT initiation, 25% of patients experienced 1 relapse, and 9% of patients experienced ≥2 relapses.
In this German real-world neurological care setting, both DMD-naïve and DMD-experienced patients initiated CT. Median disability level indicated mild disability in one functional system or minimal disability in two functional systems. One third of patients had at least one relapse in the 12 months prior to CT initiation.