Background

We designed a web-based survey to assess the willingness and interest of European neurologists working with MS to implement precision medicine in their routine clinical practice. This study is a part of the EU-funded MULTIPLEMS grant.

Objectives

1) To assess how neurologists across European countries view the role of body-fluid biomarkers in clinical practice; 2) To survey clinical practices of diagnostic work up, therapy selection and monitoring, and frequency of data collection and clinical and paraclinical measurements.

Methods

The survey had three parts: a) demographics of respondents; b) opinion of the role of predictive, diagnostic, disease-activity biomarkers and treatment-response body-fluid biomarkers in clinical practice; c) survey of clinical practice and management of MS cases (including therapy choice and use of biomarkers) by evaluating 5 clinical cases with different characteristics (therapeutic management in drug naive patients and in patients displaying different forms of remaining disease activity, as well as stopping threapy in stable diasease since long).

Results

194 neurologists across 11 European countries responded to the survey, with a mean response rate of 45%. 57.7% were male and the mean age was 49.8 years. The importance of biomarkers in clinical practice was rated from 1 (low) to 7 (high), and it was generally high: 4.1 for predictive and disease-activity biomarkers, 5.2 for treatment-response and 5.7 for diagnostic biomarkers, with neurologists in Belgium, Denmark, Spain, Sweden and UK being the most positive. Determination of cerebrospinal fluid (CSF) oligoclonal bands was considered the most established biomarker for diagnosis (98.5% of neurologists), prediction (56.7%) and disease activity (36.5%), trailed by anti-aquaporin 4 (90.7%) and anti-myelin oligodendrocyte antibodies (85.1%) for diagnosis. Anti-JC (93.8%) and varicella virus (61.9%) and anti-drug (natalizumab (74.7%) and interferon-beta (68.6%)) were considered useful in context of therapy selection and monitoring by most neurologists, while neurofilament levels in CSF and serum and vitamin D levels were less established. Therapeutic management in the five case examples varied widely, likely as a result of differences in local and national guidelines.

Conclusions

European MS neurologists express a positive opinion on the role of body-fluid biomarkers to manage MS in clinical practice, however, these seem still to have had a limited impact on therapeutic management and selection, which also varied markedly across countries. This underscores the need for further research in this area.

Background

Both induction therapy, like oral cladribine, and B-cell depletion therapy, like rituximab, are highly effective disease modulatory treatments (DMTs) in relapsing multiple sclerosis (MS). The high economic costs of the registered DMTs may limit availability of treatment and strain health budgets worldwide.
Oral cladribine is a recently approved DMT in Europe, while rituximab is used off-label, especially in Norway and Sweden. Large observational studies indicate good tolerance and treatment effects in MS and studies from other diseases indicate a good safety profile. However, to our knowledge, no phase three studies have compared rituximab with any established highly effective DMT. Formal safety data is also lacking for rituximab treatment in MS.

Objectives

To perform a prospective randomized open-label blinded endpoint multicenter non-inferiority study. The primary objective is to test whether rituximab is non-inferior to oral cladribine for treatment of relapsing MS.

Methods

In total 264 MS patients with relapsing MS will be recruited from 11 Norwegian centers and followed for 96 weeks. Inclusion criteria are having a relapsing MS diagnosis, age 18-65 years, at least one clinical relapse or one new T2 lesion on MRI within the last year and willingness to use contraception during the study period. Exclusion criteria are contraindications to either treatment, previous use of either or a similar treatment, or treatment with fingolimod or natalizumab (due to risk of rebound activity) within the last six months. The study participants will be treated with either cladribine or rituximab according to current guidelines.

Results

The primary endpoint is difference in number of new or enlarging T2 lesions between the two groups from rebaseline at 12 weeks to the end of the study at 96 weeks. Furthermore, we will study clinical course, blood samples and MRI biomarkers to provide tools for personalized MS treatment. Finally, the health economic consequences of these treatment options will be evaluated. At the time of abstract submission, 55 patients have been included across three study sites. The Covid19 outbreak unfortunately resulted in a temporary halt in inclusion from March to May 2020, but the study has now been reopened. End of study is estimated to fall 2023.

Conclusions

This study will guide clinicians and patients in future treatment choices for MS. The results will provide valuable knowledge concerning treatment strategies and can potentially have a huge impact on the costs of future MS treatments.

Background

The rapidly evolving therapeutic landscape of multiple sclerosis (MS) can make treatment decisions challenging. Novel tools using artificial intelligence (AI) can provide estimations of MS disease progression, which may aid MS therapeutic decisions. However, whether neurologists are willing to utilize information provided by AI-based models when making therapeutic decisions is unknown.

Objectives

To assess whether neurologists rely on clinical judgment (CJ) or quantitative/ qualitative estimations of disease progression provided by hypothetical AI-based models (assuming these models can reliably identify patients at high vs. low risk of disease progression) in simulated MS case scenarios.

Methods

Overall, 231 neurologists with expertise in MS from 20 countries were randomized to receive qualitative (high/low) or quantitative (85-90% vs. 15-20%) information regarding the likelihood of disease progression. Participants were presented with simulated MS case scenarios, and initially made 7 treatment decisions based on the clinical information using CJ. After randomization, participants made 10 treatment decisions using CJ and estimations of disease progression provided by AI models. We evaluated concordance and discordance of therapeutic decisions based on CJ and AI. The primary outcome was the proportion of “optimal” treatment decisions defined as treatment escalation when there was evidence of disease progression or continuing the same treatment when clinically stable. Mixed models were used to determine the effect of randomization group, case risk level, and CJ/AI. Clinicaltrials.gov #NCT04035720

Results

Of 300 neurologists invited to participate, 231 (77.0%) completed the study. Study participants had a mean age (SD) of 44 (±10) years. Of 2310 responses, 1702 (73.7%) were classified as optimal. Optimal decisions were more common for the high-risk vs. low-risk CJ group (84.5% vs 57.6%; p<0.001). There were no differences in the estimated odds of optimal responses between the quantitative vs. qualitative groups (OR 1.09; 95%CI 0.86, 1.39) after adjustment for pre-intervention responses. The estimated odds of optimal decisions for the high-risk vs low-risk CJ group was 2.96 (95%CI: 2.47, 3.56 ) after adjusting for group, pre-intervention responses, and AI-based estimations. For low-risk CJ cases, additional input by AI-based estimations was associated with a lower likelihood of optimal responses; being worse for high-risk vs. low-risk AI estimations (OR 0.235; 95%CI: 0.16, 0.340) adjusting for covariables.

Conclusions

Neurologists were more likely to make optimal treatment choices for high-risk simulated scenarios. The addition of hypothetical information provided by AI-based models- did not improve treatment decisions for low-risk cases. These results provide a framework for understanding therapeutic decision-making in MS neurologists, who are more reliant on their own CJ over AI-based tools.

Background

Therapeutic inertia (TI) is a worldwide phenomenon affecting physicians who manage patients with chronic conditions. Previous studies in Multiple Sclerosis (MS) showed TI affects 60 to 90% of neurologists and up to 25% of daily treatment decisions.

Objectives

To determine the most important factors and levels of attributes associated with treatment escalation in an international sample of neurologists with expertise in the management of patients with MS.

Methods

We conducted an international study comprised of 300 neurologists with expertise in MS from 20 countries (Europe: 59.4%, Asia/Australia: 18.3%, America: 22.3%). Participants were presented with 12 pairs of simulated MS patient profiles reflective of case scenarios encountered in clinical practice. Patient profiles included information on age, sex, previous MS history of relapses, MRI findings, desire for pregnancy, and other relevant details. We used disaggregated discrete choice experiments (a conjoint analysis), which is a standard technique used in economic research to estimate the weight of factors and attributes (e.g. categories) affecting physicians’ decisions when considering treatment selection by asking respondents to choose between pairs of options. In our study, participants were asked to select the ideal candidate (Patient A, B or neither) for treatment escalation (from first-line to second-line therapies- eg. Fingolimod, Cladribine, Monoclonal antibodies).

Results

Of 300 neurologists invited to participate, 229 (76.3%) completed the study. The mean age (SD) of study participants was 44 (±10) years. The mean (SD) number of MS patients seen per week by each neurologist was 18 (±16).

The top 3 factors (relative importance) associated with treatment escalation were: previous relapses (20%), EDSS (18%), and MRI activity (13%). Patient demographics and desire for pregnancy had a modest influence (<3%) in treatment escalation.

Participants were 13% less likely to escalate treatment for patients with EDSS >7.0 (compared to EDSS <6.0), whereas symptom severity during most recent relapse and higher number of MRI lesions at 1 year were each associated with 6% higher likelihood of treatment escalation.

We observed differences in the weight of factors associated with treatment escalation between MS specialists and non-specialists and participants practicing in European vs. non-European countries.

Conclusions

This is the first study applying a conjoint design to assess factors associated with treatment escalation and therapeutic inertia in neurologists caring for people living with MS. Our results provide critical information on factors influencing neurologists’ treatment decisions and should be applied to continuing medical education strategies.

Background

Fatigue is considered to be one of the main causes of impaired quality of life among patients with multiple sclerosis (MS). It affects family life, social activities, and education. Fatigue is one of the main reasons why many patients with MS are unable to work. To our knowledge there have been no larger studies on the prevalence of fatigue in MS in almost 20 years. Previous studies have reported a prevalence ranging between 50-90 %. We assumed that the prevalence of fatigue has changed due to changes in diagnostic criteria and the great change in treatment possibilities over these years.

Objectives

Our objective was to determine the prevalence of fatigue in a contemporary MS population in Norway, and to assess the association between fatigue and sex, age, disease course, disease severity and duration.

Methods

This is a cross-sectional study from a registry comprising MS patients in the counties Buskerud, Oslo and Telemark in Norway. Clinical, demographic and socio-economic data were obtained from the registry. Questionnaires were distributed by postal mail to all living subjects. Self-reported fatigue was assessed with the Fatigue Scale for Motor and Cognitive Functions (FSMC), and anxiety and depression was measured with the Hospital Anxiety and Depression Scale (HADS). We used the Epworth sleepiness scale (ESS) to assess daytime sleepiness.

Results

The response rate was 62.3 % (1599/2566). The prevalence of fatigue was 81.3 %. There was a significantly higher prevalence of fatigue in women than in men (82.9 % vs 77.6 %, p = 0.017). The prevalence was higher in patients aged ≥ 50 years compared with those aged < 50 years (85.7 % vs 75.4 %, p < 0.001). There was also a higher prevalence of fatigue in the group with progressive MS (87.6 % vs 80.0 % in the RR-MS group). 30 % of the patients with fatigue had concomitant anxiety/depression, versus 2.6 % in the non-fatigue group (p<0.001). Daytime sleepiness was more prevalent in patients with fatigue than in patients without fatigue (35 % versus 8 %, p<0.001).

Conclusions

Fatigue is prevalent in contemporary patients with MS and is associated with symptoms of anxiety, depression and daytime sleepiness. Fatigue was more prevalent in women, and in patients older than 50 years of age. Anxiety/depression and daytime sleepiness occurred more often in patients with fatigue.

Background

Over the past few decades there has been an improvement in the rate of disability progression in multiple sclerosis (MS) patients, and most studies relate this evolvement to the introduction of disease modifying therapies. However, several other factors have changed over this period, including access to improved MRI and newer diagnostic criteria

Objectives

To investigate changes in the natural course of MS over time in a near-complete and geographically well-defined population from the south-east of Norway.

Methods

This is a registry-based study. We examined disease progression over two decades and assessed the effect of disease modifying therapies using linear mixed-effect models.

Results

In a cohort of 2097 patients we found a significant improvement in disability as measured by the Expanded Disability Status Scale (EDSS) stratified by age, and the improvement remained significant after adjusting for time on disease modifying medications, gender and progressive MS at onset. The time from disease onset to EDSS 6 in the total cohort was 29.8 years (95% CI 28.5-31.1) and was significantly longer in patients diagnosed after 2006 compared to patients diagnosed before. In addition, we found significant differences between patient demographics, as well as time to EDSS 6 in the near-complete, geographically well-defined population compared to the rest of the cohort from Oslo and its affluent suburbs.

Conclusions

The natural course of MS is improving, but the improvement seen in disease progression in the modern MS patient may have multifaceted explanations. This is supported by our findings of changing population demographics with patients being diagnosed earlier in the disease course, but also at an older age and with less severe disease. Our study underlines the fact that historical cohorts are unsuitable for comparison with modern cohorts in MS studies. We also found significant differences in demographics and time to EDSS 6 between our geographically near-complete population and the rest of the database with the cohort from Oslo and its wealthy suburbs, which means that studies done on incomplete populations should be interpreted with caution.