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Aggressive multiple sclerosis: a matter of measurement and timing

1 German MS-Register by the German MS Society, MS Research and Project Development gGmbH [MSFP], Hanover, Germany 2 Neurological Rehabilitation Center Quellenhof, Bad Wildbad, Germany 3 Department of Neurology, Neuroimmunological Section, University of Rostock, Rostock, Germany 4 Department of Neurology, St. Josef-Hospital, University clinic of the Ruhr-University Bochum, Bochum, Germany 5 Charité Universitatsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, NeuroCure Clinical Research Center NCRC and Experimental and Clinical Research Center ECRC, Berlin, Germany 6 Department of Neurology, Medical Faculty, University Hospital of Cologne, Cologne, Germany 7 Department of Neurology, Medical University of Vienna, Vienna, Austria

We read with great interest the recently published work of Malpas et al. (2020) in which the authors identified clinical markers of patients with aggressive multiple sclerosis in a cohort of relapsing remitting multiple sclerosis (RRMS) patients with 10 years of follow-up. The authors followed the definition a confirmed Expanded Disability Status Scale (EDSS) score 56.0 within 10 years of disease onset, which was initially applied by Tintore et al. (2019) to a cohort of patients with clinically isolated syndrome. In two independent databases, MSBase (2403 cases) and the Swedish MS Registry (556 cases), the authors confirmed a similar proportion of aggressive multiple sclerosis of 6%. Predictors for aggressive multiple sclerosis were age at onset 535 years, an EDSS of 53.0 and pyramidal symptoms within the first year.
We tried to replicate the results of Malpas et al. within the data of the German MS Registry (GMSR), a nationwide registry including 430 000 patients (with at least one follow-up since 2014) recruited from all sectors of care in over 190 centres.
By applying an interval-censored proportional hazards model, the estimated overall rate of aggressive multiple sclerosis in our GMSR cohort was 8.9% for all patients (including progressive cases; n = 17 071; Fig. 1) and 7.0% if only including patients with relapsing course at onset, which is similar to previous studies. In univariate analysis of baseline covariates, age at onset [per 10 years with a hazard ratio (HR) of 2.02 and 95% confidence interval (CI) (1.91-2.14), P 5 0.001], the first year EDSS [per EDSS; HR: 3.45 (2.74-4.33), P 5 0.001] and pyramidal symptoms within the first year [HR: 4.51 (3.75-5.43), P 5 0.001] were associated with aggressive multiple sclerosis in RRMS. In multivariable analyses, however, only the EDSS after the first year and age at onset remained to be statistically significant for predicting an unfavourable course of multiple sclerosis.
Our data overall support the analysis of Malpas et al. and similar results were obtained when progressive patients were included. The progressive course per se had been identified as a risk factor for aggressive multiple sclerosis and affected patients should not be excluded unless specifically investigating forms of aggressive relapsing remitting multiple sclerosis (ARMS) (Iacobaeus et al., 2020). The ECTRIMS Focused Workshop Group further points out that a plethora of definitions of aggressive multiple sclerosis exist and there is no generally accepted definition in the literature.
We have therefore carried out further analyses of GMSR data, comparing the results for different published aggressive multiple sclerosis or highly active multiple sclerosis Advance access publication November 11, 2020 definitions (Gholipour et al., 2011;Freedman and Rush, 2016;Menon et al., 2017;Díaz et al., 2019;Tintore et al., 2019;Malpas et al., 2020;Spelman et al., 2020). These definitions vary, in part considerably, regarding the parameters to be evaluated (in addition to EDSS, also relapses, MRI data, therapy response and the follow-up time needed): For criteria based exclusively on sustained and confirmed EDSS, we considered it sufficient to observe the end of the follow-up period, which leads to different numbers of patients being analysed for each definition. The proportion of aggressive multiple sclerosis/ highly active patients varies significantly between the different definitions from 4.0% to 23.1% (Table 1 and (Fig. 1B). In addition to clinical criteria such as relapses and EDSS, we tried to sharpen the clinical relevance of these definitions and have therefore included work ability. In this regard, the different definitions showed large variability within aggressive/ highly active multiple sclerosis, ranging from 8.5% to 41.1% of patients who were not able to work (Table 1), with the highest numbers for those definitions based on EDSS.
In summary, the term 'aggressive multiple sclerosis' or 'highly active multiple sclerosis' is used differently in the literature and no agreement between multiple sclerosis experts exists on the criteria. Using the term should be carefully considered, taking into account the fact that there was little overlap among the known definitions for aggressive multiple sclerosis, even when the same dataset is used. Although it may be plausible to distinguish between a (short-term) relapse and MRI-based highly active multiple sclerosis and a long-term EDSS-based aggressive multiple sclerosis, we believe that patient-relevant outcomes, such as ability to work, may sharpen the meaningfulness of the definition.
We do not doubt the ability of the definitions to identify aggressive patients, but we believe that three aspects must be distinguished. First, there is a need to identify patients with rapid progression of the disease due to risk factors at an early stage (aggressive multiple sclerosis). Second, there is a need for long-term results that validate which patients have a high degree of disability or malignant course, e.g. measured by EDSS, as in Tintore et al. (2019) and Malpas et al. (2020). Third, it is necessary to continuously assess the severity of the disease (highly active multiple sclerosis). Welldefined definitions should be developed for all of these aspects. In addition, non-clinical factors, such as early retirement, would be important to better assess and predict the patient's status. A scoring system that includes several of the above-mentioned parameters could be helpful in predicting long-term outcomes and enabling evidence-based treatment decisions in the future.

Data availability
Anonymized data will be made available on request by any qualified investigator under the terms of the registries' usage and access guidelines and subject to informed consent of the patients.

Funding
The German MS Registry of the German MS Society was initiated and funded by the German MS Foundation and the German MS Society in 2001. It is operated by a not-for-profit company, the MSFP. In 2018, the MSFP received a grant from Merck and Novartis to support the extension of the registry and the implementation of EMA requirements. In 2019, Biogen and Celgene joined the multistakeholder funding approach to support the registry's operation and to allow the collection and reporting of data required as part of the EMA-minimal dataset. Industry funding does not result in restrictions to publish data, nor do the funders have access to raw data or influence in the scientific conduct of the registry.  .6 (6.5-6.7) 6.7 (6.6-6.8