L. Forsberg
Karolinska InstituteAuthor Of 4 Presentations
HT04.03 - Presentation 03 - Cortical atrophy in multiple sclerosis may start at puberty
Abstract
Background
Decreased gray matter (GM) volumes have been shown at the diagnosis of multiple sclerosis (MS), suggestive of early neurodegeneration processes preceding clinical symptoms. The onset and progression rate of atrophy in early stages and across large time spans in MS is still, however, uncertain.
Objectives
To analyze cortical atrophy rates in relation to the patient age vs. disease duration, to find a possible impact of age-at-onset on atrophy progression and to retropolate the time of the brain atrophy onset, based on the progression rate and trajectories.
Methods
Standardized high-resolution brain volumetric imaging was performed in the Stockholm Prospective Assessment of MS (StopMS) study. A total of 1085 MS patients (age: 11-79 years, disease duration: 0-48 years) were included and 3642 brain MRI scans were performed. FSL-SIENAX was used to evaluate the normalized cortical GM volume and further analyzed using R-libraries. Cortical atrophy rates were assessed in relation to age and disease duration respectively and stratified into five age-at-onset subgroups: <20, 20-30, 30-40, 40-50, >50 years. Locally estimated scatterplot smoothing - LOESS and linear regressions were used to calculate atrophy rates for each subgroup for the first, last and all MRI scans performed per patient (range 1-14 scans per person, median 3 scans) between the ages 17 and 60 years, and duration 0-40 years. Demographic and clinical data were available from the Swedish MS Registry.
Results
Cortical atrophy had a clearly linear progression with patient age. At the group level, the normalized cortical GM volume decreased by 3.1 ml/year. The corresponding annual cortical atrophy rates were 0.43% at age 17 and 0.53% at age 60. Patients with later onset started with lower cortical volume, following a similar linear age trajectory as patients with earlier onset. Similar findings were found for both sexes and all MS subtypes. Primary progressive MS patients, older at diagnosis, had the correspondingly lower cortical volume at their time of diagnosis. Retropolation of cortical atrophy trajectory along the linear age-related slopes to normative values suggested that MS atrophy can possibly start as early as at the age of 13 (time of puberty). Similar GM volume analyses vs. disease duration (instead of age) showed separate atrophy trajectories, where each age-at-onset subgroup started with 350 ml difference in volume at the time of onset and followed its own quasi-linear trajectory. Early age-at-onset subgroups had a higher atrophy rate with disease duration and a late age-at-onset subgroups had the lower rates.
Conclusions
Cortical atrophy progresses linearly from around the time of puberty, i.e. typically before the first reported MS symptom and appears largely independent of reported time of MS onset, diagnosis, or a subtype. Assessments of neurodegeneration in MS should preferably be analyzed in relation to the patient's age rather than the disease duration.
PS05.02 - Validation of three Secondary Progressive Multiple Sclerosis classification methods in five registries within the SPMS Research Collaboration Network
Abstract
Background
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.
Objectives
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.
Methods
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.
Results
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.
Conclusions
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
Abstract
Background
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.
Objectives
To compare characteristics of patients clinically assigned an RRMS course that are re-classified when an algorithm-based SPMS assignment method is applied.
Methods
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).
Results
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%).
Conclusions
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
Abstract
Background
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.
Objectives
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.
Methods
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).
Results
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.
Conclusions
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.
Presenter Of 1 Presentation
PS05.02 - Validation of three Secondary Progressive Multiple Sclerosis classification methods in five registries within the SPMS Research Collaboration Network
Abstract
Background
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.
Objectives
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.
Methods
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.
Results
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.
Conclusions
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.