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.

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.

Background

The Coronavirus Disease 2019 (COVID-19) pandemic has introduced uncertainties into the multiple sclerosis (MS) community and the focus so far has been the severity of infection among people with MS (pwMS) who have COVID-19. This approach has left questions about the risk of contracting disease in pwMS unanswered which has implications as society gradually returns to normal.

Objectives

To evaluate the trend of COVID-19 incidence in pwMS, their behaviour in response to the outbreak, and the effect of their demographic and clinical characteristics on the likelihood of contracting COVID-19.

Methods

The United Kingdom MS Register (UKMSR) has been collecting demographic and MS related data since 2011 from pwMS all over the UK. On 17 March 2020, existing participants of the UKMSR were asked to join the COVID-19 study. The study was also advertised through social media. In this on-going study, pwMS answer a COVID-19 related survey at participation and a different follow-up survey every two weeks depending on whether they report COVID-19.

Results

We estimate the nationwide overall incidence of COVID-19 in pwMS as 10% (n=522) among 5237 participants until 24 June 2020. The weekly incidence peaked during the 2^nd week after lockdown started on 23 March 2020 (13.2%) and remained high until it dropped to 3.5% in the 10^th week. The mean (standard deviation) age of the study population was 52.4 (11.9), 76.1% (n=3985) were female, and 95.7% (n=5012) were of white ethnicity. PwMS with a higher web-based Expanded Disability Status Scale (EDSS) score are more likely to self-isolate (odds ratio [OR] 1.389, 95%CI [confidence interval] 1.333−1.447). PwMS who are taking disease modifying therapies (DMTs) and those with progressive MS tend to self-isolate more (OR 1.259, 95%CI 1.059−1.497 and OR 1.245, 95% CI 1.013−1.531, respectively). Older age, progressive MS, and white ethnicity were associated with a lower likelihood of having COVID-19 (OR 0.969, 95%CI 0.957−0.982 and OR 0.595, 95% 0.422−0.838 and OR 0.495, 95%CI 0.347−0.705, respectively). Gender, EDSS, MS Impact Scale version 29 scores and DMTs did not alter the likelihood of contracting COVID-19.

Conclusions

To our knowledge, this is the largest community-based study of COVID-19 in pwMS worldwide. The trend of COVID-19 in pwMS is comparable to that of the UK general population. During a period with strict physical distancing measures, pwMS are not at an increased risk of contracting COVID-19.

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.

Background

Despite the well-described association between vitamin D and MS, little is known about current behaviours surrounding vitamin D and the corresponding vitamin D status in this group at a population level across the UK. During the COVID-19 pandemic, interest in the role that vitamin D might play in reducing susceptibility to and severity of COVID-19 has come to the foreground.

Objectives

To determine the vitamin D status of the UK MS population, understand the factors that influence it, and examine how vitamin D supplementation affects the risk of COVID-19.

Methods

A cohort study using the UK MS Register was performed. Self-reported data surrounding vitamin D and remotely collected biological samples were collected. 1768 people with MS (pwMS) completed a questionnaire regarding vitamin D-influencing behaviours; dried blood spots were collected from 388 of these pwMS and 309 matched controls, and serum 25(OH)D was measured. Subsequently, 592 participants from this MS cohort prospectively completed questionnaires evaluating symptoms suggestive of COVID-19.

Results

Marked differences were observed between supplementation behaviours with pwMS more likely to take supplements (72% vs 26% controls, p<0.001), and at higher doses (median 1600 IU/day vs 600 IU/day in controls, p<0.001). Serum levels of 25(OH)D were higher in pwMS than controls (71nmol/L, IQR 48 vs 49nmol/L, IQR 27, p<0.001). People with MS who did not supplement had lower serum 25(OH)D levels than non-supplementing controls (median 38 nmol/L, IQR 35 vs 44 nmol/L, IQR 21, p<0.001). 71% of those self-diagnosed with COVID-19 reported taking vitamin D vs 72% without COVID-19. Median dose for those with COVID-19 was reported as 1000 IU/day vs 2000 IU/day in those without (p=0.682).

Conclusions

pwMS living in the UK are more likely to have adequate levels of vitamin D than controls, and is driven by the higher rate and dose of supplementation across this population. This has implications on the design and interpretation of any future clinical trials with vitamin D in this population. In addition, we found no evidence that vitamin D supplementation had an impact on susceptibility to COVID-19 in this population.

Background

Anxiety and depression are more common in people with multiple sclerosis (pwMS) compared to people without MS. The unpredictable nature of the COVID-19 pandemic has caused widespread distress, but it is unknown if it would affect pwMS disproportionately.

Objectives

To evaluate the impact of the COVID-19 pandemic on the mood and well-being of pwMS in the UK and compare it to that of controls.

Methods

The UK MS Register has been collecting Hospital Anxiety and Depression Scale (HADS) data of pwMS since 2011. In the mood and well-being UKMSR COVID-19 study, we asked pwMS (n=5240) and controls (n=376) to answer questions on General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9) for depression and Revised Impact of Event Scale (IES-R) for post-traumatic stress disorder (PTSD) in addition to changes in their lifestyle and well-being during the COVID-19 outbreak.

Results

The HADS score of pwMS (n=2225) during the COVID-19 outbreak had not changed compared to the year before (mean difference 0.004, 95%CI -0.11−0.12, p=0.952 for anxiety and mean difference 0.05, 95%CI -0.05−0.15, p=0.283 for depression). The rate of anxiety (GAD-7>5) in male pwMS (37.2%) was more than controls (24.3%) (p=0.032) but was similar in female pwMS and controls. More male pwMS had moderate to severe depression (PHQ-9>9) compared to controls (28.5.4% vs 12.2%, p=0.003), but again, the rate was similar in females. More pwMS who had COVID-19, experienced anxiety or PTSD (IES-R>32) compared to those without the infection (54% vs 44%, p=0.018; 30.5% vs 22.5%, p=0.024, respectively). The rate of depression was similar in pwMS with or without symptoms of the disease. Anxiety, compared to the actual infection, was more strongly associated with subjective worsening of general health (57.1% vs 37.3%, with anxiety or COVID-19 respectively, p=0.008) or MS symptoms (61% vs 31.3%, p<0.001).

A high proportion of both pwMS and controls did not experience any change in the quality of their relationships. However, more pwMS reported worsening of their relationships compared to controls (21.4% vs 16.7%, p<0.001). The change in loneliness was similar between the two groups with 4 in 10 pwMS and controls feeling lonelier during the outbreak.

Conclusions

Anxiety during the COVID-19 pandemic is having a more profound effect on the general well-being of most patients compared to the infection itself.

Background

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.

Objectives

To compare the clinically assigned SPMS proportion to three objective SPMS classification methods in five MS registries.

Methods

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).

Results

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.

Conclusions

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.

Background

Disease modifying therapies (DMTs) are unaffordable to many people with multiple sclerosis (MS) in privately funded health care systems. Evidence, to date, to support whether socioeconomic inequality in accessing DMTs for MS exists in publicly funded healthcare systems is equivocal.

Objectives

To examine whether access to DMTs for MS depends on the socioeconomic status (SES) using a geographically diverse population through the UK MS Register

Methods

The UK MS register, which was launched in 2011, aims to capture real world data about living with MS in the UK and collaborates with many hospitals across the country. We included all patients of working age with disease duration less than 6 years who were living in England and were diagnosed with relapsing remitting MS after the age of 29, between 2010 and 2017. SES was measured by their levels of education, financial resources and English index of multiple deprivation (IMD). IMD were divided into quintiles for the analysis. Any patients who did not provide information about their SES were excluded.

Results

A total of 1060 patients registered in the UK MS registry with mean age of 44 (standard error (SE), 0.25) years and mean disease duration of 2.34 (SE, 0.05) years were eligible. 819/1060 (77%) patients were female and 388/1060 (37%) patients received DMTs. We observed that people with MS who had postgraduate education had significantly better access to DMTs compared to secondary school attendees even when the analysis was adjusted for age, disease duration and financial resources. Access to DMTs did not depend upon whether the patients were employed, homemakers, receiving disability benefits, unemployed or retired. However, patients who worked in skilled and trade professions were less likely to receive DMTs compared to those who worked as managers, directors and senior officials with an odds ratio (OR) of 0.46 (95% confidence interval (CI), 0.22-0.96) even when the analysis was adjusted for education levels, age and disease duration. People who were less deprived were more likely to be treated with DMTs; OR for receiving DMT in the 5^th IMD quintile (least deprived) was 1.96 (95% CI, 1.23-3.11) compared to 1^st IMD quintile (most deprived), when adjusted for age and disease duration. The R² value of these models showed that 3-5% of variation in accessing DMTs were dependent on these SES indices indicating that the influence of SES was small in our publicly funded national health service.

Conclusions

We found that the likelihood of receiving DMTs depend on the level of education, occupation and IMD suggesting that SES may influence the access to DMTs, in an English population.

Background

Early treatment in MS is a complex concept to convey to a naïve audience as it often needs to be considered in the absence of symptoms. There are risks involved and other life priorities to contemplate.

Objectives

To address the importance of early intervention, a film was created conveying the results of non-action. The film was produced to appeal to a broad, modern audience: short duration (164 seconds), conceptual, without dialogue and accessible across multi-formats. We assessed its success at delivering the message to people with MS (pwMS) and a general population (GP).

Methods

Three populations were included: pwMS from the UK MS Register, pwMS from outpatient clinics and a GP (Ethical approval ref: 19/LO/0282). Based upon industry standard, pre-specified outcomes were 50% viewer retention (viewing for ≥30 seconds) and 50% understanding of the concepts. The film was embedded into a website, participants were asked to review the film and the four concepts were explained. Participants answered questions about the concepts and were asked for their opinion utilising free commentary and evaluated using thematic analysis.

Results

In the MS Register population 757/959 (78.9%) pwMS had total self-perceived understanding (4/4 concepts) versus 29/42 (69%) in pwMS from outpatients and 136/149 (91%) in the GP. Understanding in all cohorts were significantly above the expected outcomes (p<0.0001) and was highest in the GP compared to pwMS (p>0.0001) In the total population 714/1150 (62%) watched ≥30 seconds with an average viewing duration of 156/164 seconds (95%), significantly above the pre-specified outcome percent (p<0.0001). Nine-hundred and eighteen of 959 (96%) provided optional free text commentary about the film. Six-hundred and ten of 918 (66%) acknowledged the role of early intervention and of taking action. In a multivariate analysis with understanding as the factor, pwMS without degree-level education and who commentated neutrally/positively, were independently associated with increased understanding of the film.

Conclusions

As part of a preventative medicine strategy, a short duration, targeted film can successfully convey the importance of early intervention to both pwMS and a GP.

Background

Fatigue is a very common and disabling symptom of multiple sclerosis (MS) that is challenging to characterize appropriately for both research and clinical practice. The emergence of the NIH PROMIS item banks provides new possibilities for the development of outcome measures that are brief and optimally targeted. Substantial evidence has accumulated regarding the use of the PROMIS SF 1.0 – Fatigue (MS) 8b short form to discriminate levels of fatigue among individuals who have MS. The short form was developed with input from MS patients and clinicians.

Objectives

To establish minimal important difference (MID) estimates and interpretation tools for the PROMIS Fatigue (MS) 8b in MS populations.

Methods

Two observational studies were performed in MS populations, a cross-sectional study at two tertiary MS centers in the US (n=296) [US sample] and a longitudinal study in the UK MS Register cohort (n=384) [UK sample]. The analysis sample included patients with relapsing- or progressive MS, and those with Patient-Reported Web EDSS <7. Minimal important difference (MID) of PROMIS Fatigue (MS) 8b T-score was analyzed based on score changes over a 52-week follow-up using an anchor-based approach [UK sample]. An interpretative guide for PROMIS scores was also developed [US sample].

Results

At baseline, study participants had a mean age of 44.5 – 49.9 years, and mean PROMIS Fatigue (MS) 8b T-score of 57.4 – 59.9. Three anchors met criteria and were used in the MID analysis [ i.e. PROMIS GHS fatigue question, GHS PHC global question, and the Fatigue Severity Scale]. The standard error of measurement [SD * √ (1 – reliability)] of baseline T-scores was 2.8. A score change of 3.4 – 4.0 points is proposed as MID criteria for minimal improvement or worsening in fatigue. A heatmap facilitating interpretation of scores based on fatigue concerns on individual items was developed. For example, a T-score of 60 represents a fatigue level characterized by (often) getting tired easily, (sometimes) being too tired to think clearly, and (some-) interference with physical functioning, in the last 7 days.

Conclusions

This research extends the evidence underpinning the applicability of the PROMIS Fatigue (MS) 8b in routine clinical practice and clinical research. The score interpretation guide may aid the integration of PROMIS scores into clinical decision-making as well as facilitate clinician-patient communication. MID estimates will be useful in evaluating fatigue over time.

Background

There is need to respond to the challenges of developing a robust measurement technique for self-reporting of the level of physical functioning by patients with multiple sclerosis (MS) to help with identifying strategies for improving such outcome. The emergence of the NIH PROMIS item banks has opened new possibilities for developing instruments that are brief, optimally targeted and, potentially, have high precision. This holds promise for addressing unmet measurement needs in MS populations e.g. subtle physical disability changes.

Objectives

To describe the development, validity and applicability of a multiple sclerosis (MS)-specific PROMIS short form for use in relapsing and progressive MS types, the PROMIS SF v2.1 – Physical Function (MS) 15a.

Methods

A mixed-methods sequential design was followed in this research. Step (1) Concept elicitation (CE) interviews were carried out with MS patients (n=14). Step (2) results from the interviews were mapped to the PROMIS physical function item bank, to identify items relevant for MS patients. Subsequently, neurologists (n=6) rated the relevance of the item pool. Step (3) cognitive debriefing (CD) interviews were performed with MS patients to confirm the comprehensiveness, relevance and language clarity of the draft short form (n=48). Step (4) Further item reduction and psychometric evaluation was performed in two observational studies [cross-sectional study at two MS tertiary centers, n=296 (US); 96-week longitudinal study in UK MS Register cohort, n=558 (UK)].

Results

The initial item shortlist (48 items) from the NIH PROMIS item bank was revised in sequential steps, considering 1) optimization of coverage of the underlying concept, 2) results from CD interviews and 3) results from psychometric item-level analysis. Fifteen items were retained in the final short form.

Cronbach’s alpha (> 0.9) and ICC of test-retest scores (5 to 27 days) (> 0.9) indicated the short form’s strong reliability. Convergence validity was demonstrated by moderate-to-strong correlations with related PRO measures as well the EDSS (rho = ± 0.5 to 0.9). The short form discriminated between groups of patients according to levels of physical health and other criteria. A score banding system referencing responses on the individual items as anchors, was generated, to facilitate meaningful score interpretation.

Conclusions

The PROMIS PF (MS) 15a is a reliable and valid short form for assessing physical function with self-report in people living with MS. The inclusion of input from MS patients and neurologists during its qualitative phase of development, ensured comprehensiveness and relevance for both relapsing and progressive MS types.