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A Systematic Review of the Validity and Reliability of the Patient-Determined Disease Steps Scale

Assessing Access to Five Types of Insurance by People with Multiple Sclerosis Using a Cross-sectional Online Survey

NARCOMS and Other Registries in Multiple Sclerosis

Guest Editorial - Volume 23, Issue 6 - November 2021

Shared Decision Making and Autonomy Among US Participants with Multiple Sclerosis in the NARCOMS Registry

Trigeminal Neuralgia Commonly Precedes the Diagnosis of Multiple Sclerosis

 A wearing-off effect has been reported in people with multiple sclerosis (MS) receiving ocrelizumab and other monoclonal antibodies. We sought to describe the real-world occurrence of wearing-off effect among people with MS in Canada treated with ocrelizumab.

 Canadian self-reports coded to the Medical Dictionary for Regulatory Activities preferred term 

) between November 5, 2008, and March 15, 2023, were identified from the Roche Global Safety Database. Cases were then linked to patient-level data from the Canadian Roche Patient Support Program (COMPASS). Only people with MS who had received 3 or more doses of ocrelizumab were included.

 A total of 10,055 people with MS in Canada received 3 or more doses of ocrelizumab within COMPASS. 

was reported 140 times among 138 unique cases (1.3%) over an average of 7.4 infusions. Discontinuation of ocrelizumab was generally uncommon. In the overall COMPASS population, 11.4% (1143 of 10,055) discontinued ocrelizumab. Among those who reported 

, 15.9% (22 of 138) discontinued while the majority (116 of 138; 84.1%) continued ocrelizumab treatment. Of individuals reporting the adverse event of interest, those with relapsing-remitting MS more frequently remained on therapy (98 of 112; 87.5%) compared with those with primary progressive MS (18 of 26; 69.2%).

 A wearing-off effect was infrequently reported and did not limit treatment among people with MS in the real-world COMPASS patient support program.

 The authors thank all people with MS enrolled in Roche Canada COMPASS. The medical writing support provided by Stevie Kenyon of Placencia Holdings (Hamilton, Ontario, Canada) is also appreciated.

In the past 3 years, Sarah A. Morrow, MD, has served on advisory boards/had speaking engagements for Biogen Idec, Bristol Myers Squibb/Celgene, EMD Serono, Greenwich Biosciences, Novartis, Roche, Sanofi Genzyme, and Teva Neurosciences; has received investigator-initiated grant funds from Biogen Idec, Novartis, Roche, and Sanofi Genzyme; and has acted as site primary investigator for multicenter trials funded by Bristol Myers Squibb/Celgene, EMD Serono, Novartis, roche, and Sanofi Genzyme. Victor Gitman, PharmD; Sofija Spasojevic, PhD; Jessica Rassi, MSc; Noemi Pasquarelli, PhD; and Kocho Fitovski, MD, are employees and shareholders of Hoffmann-La Roche/F. Hoffmann-La Roche. Galina Vorobeychik, MD, has received research support, educational grants, and/or honoraria from Alexion, Berlex, Biogen Idec, Bristol Myers Squibb/Celgene, EMD Serono, Novartis, Roche, Sanofi Genzyme, and Teva Neurosciences.

Hoffmann-La Roche (Mississauga, Ontario, Canada) sponsored this research and writing services for the preparation of the manuscript. The company, in collaboration with independent authors, was also involved in the study design, collection, analysis, and interpretation of data; writing the report; and the decision to submit the article for publication.

Presented as an abstract/poster at the European Committee for Treatment and Research in Multiple Sclerosis 2022; October 26 to 28, 2022; Amsterdam, Netherlands.

Multiple sclerosis (MS) is a chronic, neurologic, inflammatory disease affecting approximately 90,000 Canadians.

 MS can affect various parts of the central nervous system, leading to a range of possible symptoms (eg, fatigue, lack of coordination, sensory symptoms, vision problems, bladder problems, cognitive impairment, mood changes). In Canada, approximately 90% of MS cases are relapsing-remitting (RRMS),

 characterized by reversible episodes of neurological dysfunction and disability. However, damage from these events can accumulate over time, with resulting lesions in the brain and spinal cord.

 In 10% of Canadian people with MS, the disease is progressive from onset (primary progressive MS [PPMS]).

Although there is no cure for MS, current therapies support people with MS in reducing disease activity, delaying progression, and gaining better symptom control.

 Among a broad class of disease-modifying therapies (DMTs) are the higher-efficacy monoclonal antibodies (mAbs) alemtuzumab, natalizumab, and 3 anti-CD20s: ocrelizumab, ofatumumab, and ublituximab.

 Each has a unique structure, mechanism of action, dosing regimen, and safety profile.

 Ocrelizumab, a humanized mAb that selectively targets CD20-expressing B cells, is approved in Canada for the treatment of RRMS and PPMS.

 After initial dosing of a split, twice-administered 300-mg infusion, ocrelizumab is administered at a single fixed dose (600 mg) every 6 months.

Natalizumab, ocrelizumab, and ofatumumab have been linked with reports of a therapeutic phenomenon called 

 A wearing-off effect is described as the experience of MS symptoms, such as fatigue, in the days or weeks prior to the next scheduled mAb infusion and a disappearance of such symptoms following receipt of the treatment.

 It has been reported at varying frequencies (16%-67%), which may be a result of different case definitions and/or assessment methods.

 The wearing-off effect is often referred to as a phenomenon for which research has failed to elucidate either the true cause or consequence of the effect.

 This is notably different from disease reactivation or rebound, which has been reported and studied extensively following natalizumab and fingolimod discontinuation.

 For natalizumab, findings from a study of the wearing-off effect associated the event with lower α

-integrin receptor occupancy on circulating leukocytes, suggesting a decreased treatment effect.

 For ocrelizumab, research suggests that the reported wearing-off phenomenon is not related to dose interval, B-cell count (remains depleted), symptom burden, or clinical efficacy but may be correlated with higher body mass index (BMI).

Considering the differences in reported frequency as well as within patient variability of wearing-off effect reports among people with MS treated with ocrelizumab, further investigation was deemed worthwhile. In Canada, the provision of ocrelizumab for MS through a national patient support program presented an opportunity to further study wearing-off effect events in a large population of people with MS treated with ocrelizumab in a real-world setting. The primary objective of this study was to determine the frequency with which the wearing-off effect occurs during real-world treatment with ocrelizumab and, secondarily, to characterize how the event affected the course of treatment, if at all.

This is a retrospective, observational study of Canadian people with MS treated with ocrelizumab enrolled in the Canadian Roche Patient Support Program (COMPASS) and reporting wearing-off effect (within the Roche Global Safety Database).

COMPASS is a patient support program in Canada, sponsored by the manufacturer of ocrelizumab, that supports the provision of the drug to people with MS. All people with MS in Canada receiving ocrelizumab would at some point in their care be enrolled in COMPASS. The Roche Global Safety Database is a centralized repository for reports of adverse events (AEs) received for products manufactured by F. Hoffmann-La Roche Ltd.

AEs were voluntarily reported, meaning event information was volunteered in an unprompted manner. 

) was the Medical Dictionary for Regulatory Activities v24.1 (MedDRA) highest-level preferred term used in the analysis to capture wearing-off events. Aligned with routine pharmacovigilance processes, medical coders selected the most appropriate lowest-level term from the MedDRA that accurately reflected the reported verbatim information. Medical judgment was applied to assign a MedDRA term that represented the reported concept when the verbatim term was not an exact match to 

 Examples of verbatim terms that were coded to the preferred term (

. Individual case safety reports coded to the MedDRA preferred term 

were extracted from the Roche Global Safety Database (collected from November 5, 2008, to March 15, 2023) and linked with data from the COMPASS program using unique patient identification numbers or initials and date of birth (

There was no imputation of data; cases with missing identifying information were excluded from the analysis. Reports not linked to the COMPASS program (eg, those from clinical trials) were excluded from this study. Only adults (aged ≥ 18 years) with MS who had received at least 3 doses of ocrelizumab were included in the analysis of TRS. This ensured those included in the analysis had received 2 initial doses (300 mg each) and, approximately 6 months later, a third dose (600 mg; full dose), allowing for at least one 6-month dosing interval in which TRS might occur. TRS events are herein referred to as 

in keeping with the common literature, as terms synonymous with reports of wearing-off events were coded to TRS as per MedDRA.

The primary variables of interest for this study included reports of wearing-off effect, indication for treatment, therapy status (collected by COMPASS; eg, 

[within the 6-month dosing interval and intends to receive the next ocrelizumab infusion] or 

[exceeded the 6-month dosing interval or does not intend to receive the next ocrelizumab infusion]), and reason for treatment discontinuation (eg, unknown reason, physician recommendation, AE with program drug, financial reason, switched to another therapy, or other). The Roche Global Safety Database served as the primary source for the following data: AE information (seriousness and outcome), sex at birth, and age. The COMPASS program provided baseline demographics, including data related to treatment history, current therapy status, ocrelizumab dosage, dosing interval treatment indication, and supplementary information on sex and age if unavailable in the AE report. Individuals were stratified by indication for ocrelizumab therapy (ie, RRMS or PPMS). Standard follow-up conducted by case managers in the COMPASS program includes a call after the individual is medically cleared by their neurologist, a call 5 business days prior to the scheduled infusion, a call 2 business days after the infusion, and a 4-month check-in call after the last infusion (ie, 2 months before the next).

This study involved the secondary use of personal data; hence, informed consent was not feasible nor required. A waiver of consent was granted by Advarra (May 3, 2022). All people with MS participating in the COMPASS program consented to sharing their personal information (including personal health information) with Roche and the possibility that this information would be used in an aggregated manner for publication. Still, precautions were taken to protect participant anonymity, including aggregating and anonymizing/pseudonymizing final data and ensuring linkage back to the individual participant was impossible or tightly controlled. The study protocol was reviewed and approved by the Advarra Institutional Review Board (approval number: MOD01320274).

Analyses were conducted using Python 3.8.8. For continuous variables, measures of central tendency (medians and means) and dispersion (SD and range) are reported. The COMPASS database provided a total number of individuals exposed to ocrelizumab (a denominator), and the Roche Global Safety Database, after exclusions, provided the number of individuals affected (the numerator). This enabled the reporting of frequencies and percentages for each categorical variable. All data are reported using descriptive statistics.

As of March 15, 2023, a total of 10,567 people with MS had received at least 1 administration of ocrelizumab through the COMPASS program, with 10,055 having received at least 1 full dose. Of those, 138 unique cases and 140 reports of wearing-off effect (2 individuals reported wearing-off effect twice) were identified in the safety database and linked to COMPASS, representing 1.3% of the estimated total exposed population (Figure S1). Reports were primarily received by patients or other non–health care professionals (see 

Characteristics of the study and source cohorts are outlined in 

Patients reporting a wearing-off effect received an average of 7.4 infusions, with a mean time between full doses of 6.2 months. Generally, people with MS treated with ocrelizumab reporting wearing-off effect had similar disease and treatment characteristics as those of the total exposed population (Table 1). The wearing-off effect occurred in people with PPMS and RRMS in proportions similar to the overall study makeup (Table 1). The majority of individuals with PPMS were treatment naive prior to receiving ocrelizumab. Mean ocrelizumab dosing interval was similar between the groups, with the majority receiving ocrelizumab every 6 months with no variation (IQR, 0; Table 1). Duration of therapy and number of infusions received were higher in the group reporting wearing-off effect (Table 1).

All reports of wearing-off effect were nonserious (

Overall, 11.4% of the total exposed population and 15.9% of people with MS reporting wearing-off effect discontinued treatment (

The discontinuation rate was higher in those with wearing-off effect and PPMS vs RRMS (30.8% vs 12.5%, respectively; Table 3). Reasons for discontinuation in people with MS reporting wearing-off effect were similar to those of the overall COMPASS population (Table 3).

A comparison of people who reported wearing-off effect and continued vs discontinued ocrelizumab is outlined in 

The groups had a similar ocrelizumab dosing interval (every 6 months). People who reported wearing-off effect and discontinued ocrelizumab were more likely to be older, were more likely to be men, and had a lower overall duration of treatment than those who continued ocrelizumab.

AEs reported in conjunction with the wearing-off effect are detailed in 

We investigated reports of a wearing-off effect in people with MS in Canada by combining events from the global safety database with patient-level data from the national COMPASS database. Given that all people with MS receiving ocrelizumab outside of clinical trials in Canada receive it via COMPASS, the data set allowed for a reliable estimate of total Canadian exposure. This database, coupled with the Roche Global Safety Database, provided a useful means of analyzing the wearing-off effect phenomenon in Canada. We observed that wearing-off effects coded to 

were reported by 1.3% of the studied population and were generally not treatment limiting, with 15.9% of people with MS who reported wearing-off effect discontinuing ocrelizumab.

Studies of wearing-off effect published to date have ranged from case series

 to prospective, phase 4, nonrandomized, multicenter trials (N = 376).

 When surveyed, people with MS treated with natalizumab have reported a wearing-off effect at a frequency of 37% to 67%.

 Similarly, a wearing-off effect has been reported in 51% to 61% of people with MS receiving ocrelizumab.

 These prospective studies related to ocrelizumab (88-100 participants) used a wearing-off questionnaire and noted the potential for overreporting due to enhanced recall and reporting bias.

In contrast, our study presents the largest cohort of people with MS yet studied for the wearing-off effect (N = 10,055) using spontaneous AE reporting rather than topic-specific questionnaires. Spontaneous AE reporting has been shown to underrepresent the prevalence of an AE compared with active monitoring (or true incidence).

 Although in some cases, rare AEs may be subject to less underreporting,

 in the case of wearing off, underreporting may be amplified given its subjective nature and relative nonseriousness. Interestingly, a retrospective chart review from British Columbia, Canada, found a wearing-off phenomenon recorded in 16% (11 of 69) of patient charts.

 Our data show that the spontaneous reporting of wearing off in a large real-world population is lower than that found in prospective studies. We suspect the true incidence of wearing off lies somewhere between the rate of spontaneous reports seen in our study and the frequency of reports solicited in prospective studies.

In the prospective study by Toorop and colleagues, treatment satisfaction did not differ between those reporting wearing off and those not reporting it

; however, in the multi-mAB study noted previously, wearing off was associated with reduced treatment satisfaction scores, and 20% of participants noted they had considered switching to another DMT.

 Uniquely, our data report on treatment status and reasons for ocrelizumab discontinuation. Importantly, wearing-off events were not reported as the reason for ocrelizumab discontinuation, and most people with MS affected remained on treatment (84.1%). Furthermore, wearing-off events were confirmed to be nonserious in nature for all in our study. The majority received ocrelizumab at 6-month intervals, and overall duration of therapy was similar in the total COMPASS population as it was among those who reported wearing off and discontinued treatment.

The potential cause of wearing off remains unknown. Findings from studies related to ocrelizumab used at extended dosing intervals have shown a maintenance of clinical efficacy, even with altered B-cell repopulation.

 In our study, a median dosing interval of 6 months was observed in both people with MS reporting wearing-off effect as well as the total exposed population, which is in line with the recommended dosing interval of every 6 months.

Given this consistency between groups, we were unable to observe any impact of dosing interval on wearing off.

Another theory to explain wearing off that has been explored is a decreased pharmacological effect. In the SymBOLS study (NCT04855617), no correlation was found between serum neurofilament light chain (sNfL) or ocrelizumab serum levels and symptom burden, suggesting wearing off is not a result of subclinical disease activity.

 found wearing-off reports were associated with higher levels of CD8 and CD3/CD27 lymphocytes (ie, reduced immunomodulation) and increased plasma NfL levels (ie, neuroaxonal damage); however, these were not correlated with clinical or radiological disease activity nor ocrelizumab serum levels, so a causal effect was not established. Results from a cross-sectional study by Meca-Lallana et al found no correlation between sNfL, CD19+, baseline Expanded Disability Status Scale score, age, progression, or relapse in people with MS treated with ocrelizumab experiencing a wearing-off effect.

 Finally, Toorop and colleagues observed a correlation between higher BMI and a wearing-off effect that did not appear correlated with B-cell count.

They speculated that higher rates of clinical disability experienced by people with MS and obesity may be responsible for greater MS symptom fluctuation.

The prevailing hypothesis, based on current evidence, is that the wearing-off phenomenon may be a subjectively perceived lack of effect or disease-related symptom fluctuations misattributed to treatment.

The low rates of unprompted reports observed in our study support this. In CASTING, a phase 3b study (NCT02861014), the patient-reported outcome tool SymptoMScreen, which includes elements such as fatigue, cognitive function, and sensory symptoms—all in common with wearing-off effect symptoms—was applied.

 People with MS who previously had a suboptimal response to 1 or 2 DMTs had significant improvement in SymptoMScreen scores, which were observed 24 weeks into ocrelizumab treatment and maintained over 96 weeks.

 Furthermore, results from the SymBOLS study of 103 people with MS treated with ocrelizumab failed to show correlation between wearing off and meaningful symptom changes throughout the infusion cycle as measured by Quality of Life in Neurological Disorders short forms, SymptoMScreen, and the Work Productivity and Activity Impairment Questionnaire at the beginning, middle, and end of the ocrelizumab treatment cycle.

 Importantly, the significant intra- and interindividual symptom variability associated with the MS disease course (regardless of treatment)

 is likely to affect the ability of prospective studies to objectively and consistently capture wearing-off phenomenon within a group over time. Results from a recent study of wearing-off effect with 4 mAbs found wearing off to be associated with symptoms of depression, which may support the theory that it is a psychological rather than biological phenomenon.

The present work is characterized by some limitations. Inherent to the nature of safety databases, the extracted data require careful interpretation due to the varying quality of AE reports, which could in some instances have missing, nonverifiable, and/or incomplete information. This also precluded the analysis of comorbidities (such as BMI and laboratory parameters) that may overlap with wearing-off effect. However, the COMPASS data supplement many other data points potentially missing from AE reports.

The calculation of population-based AE rates was not feasible because voluntary AE reporting is unprompted and, particularly for nonserious events, prone to be underreported.

 Given the unsolicited and voluntary nature of the information retrieval, there is a possibility that some wearing-off symptoms were not reported, potentially leading to an underestimation of the true frequency as discussed previously. Furthermore, although the preferred term 

captured a broad range of synonymous terms, other common MS symptoms (eg, fatigue) reported independently of the analyzed preferred term may not have been coded in the Roche Global Safety Database as 

, further contributing to the potential underestimation of the frequency of wearing off.

Despite the above considerations, our data provide insights into a phenomenon that is difficult to objectively measure. Wearing-off event analysis can vary by the definition of the reported event, use of a biological/symptomatic surrogate, timing/interval of data collection, study design and resulting biases, and individual awareness of the effect. These are all factors at play when considering the results of this study in the context of the limited literature on the topic.

Although these findings support the provision of ocrelizumab according to the recommended dosing schedule, with no observed impact due to wearing-off effect, an opportunity to better understand the phenomenon remains. In addition to routine pharmacovigilance assessment for lack of efficacy (including wearing-off effect), longitudinal studies designed to minimize reporting bias and monitor symptom recrudescence and biological markers over the course of treatment may be insightful. Two ongoing phase 3 studies investigating ocrelizumab administered at higher doses may provide additional insights into symptom control under other clinical circumstances.

In this large and representative population of people with MS in Canada treated with ocrelizumab, reports of wearing-off effect were infrequent (< 2%). Observed symptoms and treatment patterns in people with MS reporting wearing-off effect were nonserious and support the continuation of therapy according to label recommendations.

Wearing-Off Effect Reports in People With Multiple Sclerosis Receiving Ocrelizumab

Patient-generated data are a cornerstone of individualized multiple sclerosis (MS) treatment. MyMS, an interface for patient-reported outcomes (PROs) was developed by the Finnish MS Register to enable systematic collection of PROs.

MyMS collects data on demographics, lifestyle factors, disease-related factors, and validated questionnaires, including the Quality of Life Questionnaire (15D), the Multiple Sclerosis Impact Scale (MSIS-29), and the Fatigue Severity Scale (FSS). At the end of 2020, the patient-reported Expanded Disability Status Scale (PREDSS), the EuroQOL-5 Dimension (EQ-5D), the Fatigue Scale for Motor and Cognitive Functions (FSMC), and the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) were added.

As of January 1, 2023, 1201 individuals with MS (79% female) have added data to MyMS. Of the validated PRO measures (PROMs), the 15D, MSIS-29, and FSS are the most used. The mean PREDSS score is 3.0 and median disease duration is 6.4 years. According to the existing PROMs, patients report mildly compromised quality of life and problems with fatigue and cognition.

The patient interface of the Finnish MS Register consists of data from 17 of 21 counties with well-being services. The interface is used by 10% of Finnish individuals with MS. The addition of the PREDSS, EQ-5D, FSMC, and MSNQ to the interface has increased health care professional and patient interest in the use of PROMs. We suggest that PROs should be integrated into electronic health records to improve shared decision-making and diminish documentation burden.

The authors gratefully acknowledge the contribution of the StellarQ IT team that built and continuously refines the Finnish MS Register platform. All members of the steering committee of the Finnish MS registry as well as patients who have participated in the development of MyMS are gratefully acknowledged.

High-quality patient registers are needed to improve the monitoring and treatment of progressive diseases sucha as multiple sclerosis (MS). MS registers are in use in many European countries,

 and the need to further develop register-based data collection is recognized worldwide.

 Registers allow individualized follow-up by providing systematic data on disease history, real-world data on the natural history of the disease, as well as data on treatment effectiveness, tolerability, and safety.

 They may also be used to predict an individual’s risk of conversion to secondary progressive multiple sclerosis (SPMS).

 Optimally, registers combine patient-reported data with data contributed by health care professionals (HCPs).

Along with the development of clinician-based registers, there is a growing need to implement patient engagement options, combining objective disease data with subjective patient-reported outcomes (PROs). This would promote patient autonomy, shared decision-making, and cost-effective individualized care.

 A PRO is any report of the status of an individual’s condition that comes directly from the individual, without interpretation by anyone, such as a clinician. PRO measures (PROMs) are standardized tools such as surveys, scales, or single-item measures. It is important that HCPs and the treatment team know how individuals perceive their disease, quality of life (QOL), treatment effects, and adverse events, and that means measuring outcomes that matter most to people with MS.

 Systematic collection, storage, and use of PRO data are likely to improve disease management and help the treatment team and the patient determine the best treatment options together.

Finland’s national MS register was launched in 2014

 to enable systematic disease monitoring as well as to monitor disease incidence, prevalence, and progression. A PRO interface was added in 2017 to enhance patient-centeredness and autonomy. Individuals are able to record data on medication usage, suspected relapses, lifestyle factors, and QOL, as well as keep track of disease severity, symptoms, and impact. The interface allows patients to follow their disease in a visual format and acts as a communication tool with the treatment team.

The objective of this study was to describe the contents and status of MyMS, the PRO interface of the Finnish national MS register. We illustrate the core variables and data collected by MyMS at the beginning of 2023. We also discuss future challenges, perspectives, and needs related to PRO-based data collection.

The Finnish MS Register is a browser-based register for public health care organizations.

 During the patient visit, it is the neurologist’s primary user interface, integrated into the hospital’s electronic patient record (EPR) system. HCPs log on to the MS register via the hospital’s EPR system with a single sign-on identifier, which automatically redirects them to the individual’s registry view. It is also possible for the structured patient narrative to automatically transfer to the neurology interleaf of the EPR, which avoids having to record patient information in 2 different systems. The PRO data in the patient interface are displayed directly on the clinician’s interface.

The use of the register is voluntary, and each county with well-being services decides whether to acquire it. The development of the register, the steering committee, and the core features of the clinician-based register are described elsewhere.

 As of January 2023, 17 of 21 of Finland’s counties with well-being services, which includes all 5 university hospitals, use the register, and most of them have integrated it into their EPR system. In January 2023, the number of patients in the register was 11,349, which was approximately 90% of individuals with MS in Finland. Register funding is based on licensing fees paid by the counties to the software service provider, StellarQ Ltd (

The interface for PROs is available to all patients who have enrolled in the national MS register. MyMS is a secure log-in service with a user-friendly and graphically illustrative interface (

). It includes the following PROs: identification data (name, date of birth, sex), background data (heredity, education, employment), lifestyle factors (smoking, use of alcohol), suspected relapse notation, medications, comorbidities, and requests for assistance and rehabilitation, as well as standardized questionnaires on disease severity, impact, symptoms, disability, and QOL. The standardized PROMs include the patient-reported Expanded Disability Status Scale (PREDSS),

 the Quality of Life Questionnaire (15D),

 the Multiple Sclerosis Impact Scale-29 (MSIS-29),

 the Fatigue Scale for Motor and Cognitive Functions (FSMC),

 and the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ).

 In case of interruption, it is possible to complete a questionnaire within 24 hours. At the end of 2020, the PREDSS, the EQ-5D, the FSMC, and the MSNQ were added to the register; all the other measures were present from the launch of the interface. Approximately 10% of Finnish individuals with MS use MyMS.

Individuals with MS learn about MyMS mainly from MS nurses working in hospital MS clinics. The nurses are provided with written instructions on how to introduce the interface and the PROs, and written instructions are also available as handouts. The Finnish MS associations also tell their members about using MyMS to follow their disease and participate in their treatment.

National level patient-reported data were collected from the real-time pseudonymous database. Patients permit data utilization for study purposes, as long as data are reported in aggregated, anonymous form. This is ensured via a formal consent that is collected through MyMS when the patient begins to use the interface. Data extraction also includes date of MS diagnosis, which is mandatory clinical information to get access to the patient interface. StellarQ is the data processor for all data extracted.

Data extraction included patient-reported data from January 1, 2017, through December 31, 2022. Data counts and percentages of patients with data in MyMS as well as mean, standard deviation, median, and quartiles for the latest scores were calculated using nonmissing data. No imputation was needed. Date of first data entry in the patient interface was considered the index date to calculate age, disease duration, and user count progression. All data analyses were done using RStudio (version 2023.03.0).

A total of 11,349 MS patients (G35) and 692 patients with unspecified demyelinating disease of the central nervous system (G37.9) were registered with the Finnish MS Register as of January 2023. There are 4 well-being services counties that do not use the MS register (

; coded as 1, 7, 8, and 19). In 12 counties, MyMS is considered inactive (ie, coverage under 10%). There are 3 counties (3, 6, 14) with MyMS coverage exceeding 20%.

MyMS was used by 1201 patients in January 2023. The number of MyMS users has increased linearly since it was launched in 2017. 

 shows the cumulative progression of MyMS users as well as the cumulative progression of filled documents from 2017 to the beginning of 2023.

Of the 1201 MyMS users, 79% are women, and there was a median disease duration of 6.4 years and 13.9 mean years of education based on self-report (

 describes the MyMS variables, how many times the variable has been recorded in the register, and the percentage of patients who have the information included in their data file. The most actively reported PROs were lifestyle factors and background information. The PROMs that were included since the launch of the patient interface have been used the most; 74.6% of respondents with MS have filled out the 15D, 52% the MSIS-29, and 51% the FSS. The scales added in the register later have been filled out by individuals with MS as follows: the PREDSS by 39.4%, the FSMC by 35.0%, the EQ-5D by 31.6%, and the MSNQ by 18.1%.

The mean PREDSS score (n = 473) is 3.0, which means the average patient has no walking ability limitations, but has other significant MS-related problems that limit daily activities (

). The mean EQ-5D (n = 380) and 15D scores (n = 896) were both 0.8, indicating mildly compromised QOL.

 The mean MSIS-29 scores (n = 624) were between 26.2 and 28.5, which indicates few problems

 The mean FSS score (n = 613) was 4.2, equating to mild self-perceived fatigue.

 In contrast, the FSMC scores (n = 420) seemed to indicate severe overall fatigue (mean score 63.1) as well as moderate motor (means core 31.4) and cognitive fatigue (mean score 31.7).

 The mean MSNQ score (n = 217) was 35.3, which means that the patient perceives problems with cognitive functions.

Seven years after its launch, the Finnish MS Register covers the majority of Finnish MS patients. It is increasingly being adopted as a part of clinical practice following the national treatment guidelines,

 and efforts to achieve complete coverage are ongoing. PROMs, especially standardized and validated ones, are growing in importance because individualized patient-centered treatment is the gold standard of high-quality care.

 has highlighted the need to improve communication between patients and HCPs to promote patient participation and self-management, as well as to enable access to high-quality information.

There are several national MS registries in Europe that differ from each other with respect to objectives, structure, collected data, and patient and clinician involvement.

 The registries were established between 1956 (Denmark) and 2014 (Finland). In 2017, the number of patients in the registries varied from 1000 to approximately 50,000.

 Registries are typically kept by academic research institutions, patient organizations, or health care organizations.

 Based on a review published in 2014, physician-based outcome measures such as the Expanded Disability Status Scale (EDSS) were used in all 20 identified European registries, whereas data from patients’ perspectives were only collected in 6 registries.

 According to results of a more recent survey published in 2019, 7 of 19 identified MS registries include patient-derived measures.

 The MSIS-29 was used in all 7 registries, and 6 registries included PROMs on fatigue, 4 of those the FSS. The North American Research Committee on Multiple Sclerosis (NARCOMS) registry is one of the few patient-driven registries. In NARCOMS, patients fill out questionnaires online or by mail to a coordinating center.

 In contrast to the patient interface of the Finnish national MS registry, data collection in NARCOMS initially occurred only at enrollment, and longitudinal semiannual data collection began in 2020.

 electronic health technologies could play an increasing role in the systematic use of PRO data. The patient interface of the Finnish MS Register is a good example of an e-health solution that enables systematic collection of patient experience. Active use of the data in MyMS together with that in the clinician-based MS register is 1 way to improve shared decision-making. Systematic self-report is a way to empower patients to take responsibility for their disease and commit to treatment, rehabilitation, and beneficial lifestyle choices.

 When the patient uses MyMS, the treatment team can compare the clinician-rated EDSS

 score with the corresponding PROM and the PREDSS

 and then discuss any discrepancies with the patient. The PREDSS has shown high correlation with the clinician-rated EDSS.

 Moreover, the information on patient-perceived symptoms and impact of the disease is readily available to the team, as it is displayed on the clinician interface.

Because many MS-related symptoms are invisible and difficult to diagnose in their early phases, patient reports are critical. Based on a European registry sample of almost 14,000 individuals with MS, Kobelt and colleagues

 showed that self-reported fatigue and cognitive symptoms reduce working capacity. In MyMS, patients have the opportunity to fill out the MSNQ

 to evaluate and follow their cognitive symptoms, the FSS

 to evaluate fatigue severity, and the FSMC

 to evaluate the characteristics of their self-perceived fatigue. The clinician can combine the MSNQ with the results on the objective measure of information processing speed, the Symbol Digit Modalities Test,

 which is recorded in the clinician-based register. Thus, MyMS may help identify patients who need support to manage invisible symptoms such as fatigue and cognitive problems. At best, longitudinal and systematic patient reporting is a pathway to react to treatment urgencies without delay.

The present sample represents most of the counties in Finland with well-being services, although the coverage is uneven. Women are more active MyMS users than men. MyMS users reported mild disability as rated with the PREDSS (mean score 3.0). QOL was reported by both the 15D and the EQ-5D to be mildly compromised. The MSIS-29 showed mild physical and psychological disease impact. Contrary to the FSS showing mild self-perceived fatigue, the FSMC showed severe overall fatigue and moderate motor and cognitive fatigue.

 At the end of 2020, new validated instruments were implemented into MyMS mainly to help evaluate invisible symptoms, such as fatigue with the FSMC and cognitive problems with the MSNQ. It is possible that patients who filled out the measures added in 2020, the PREDSS,

 have more pronounced cognitive and fatigue concerns, which would explain why the FSMC shows more severe fatigue than the FSS. Further, the FSMC covers cognitive and physical aspects of fatigue equally, whereas the FSS focuses on physical aspects of fatigue. This may be another reason for the discrepancies in the results of the fatigue questionnaires.

Patients can use MyMS whenever they want. The interest in self-reporting is growing alongside the need for and interest in early intervention and shared decision-making, especially due to the increasing number of treatments. Patients increasingly look to PROMs to convey their lived experiences and multifaceted challenges. The lack of knowledge on the use of PROMs and difficulties utilizing PROM data in often fast-paced clinical decision-making may have previously hindered the use of patient reporting.

Efforts to improve user experience, including the development of a mobile application, are ongoing. By adding feedback and guidance on the validated questionnaires, MyMS could become a source of reliable information and a self-management tool. Implementation of patient-reported experience measures to evaluate treatment satisfaction is also a future milestone in the development of the patient interface.

As yet, there is no systematic national procedure to present MyMS to MS patients in neurology clinics. Some clinics do have a systematic approach, particularly in southwestern and eastern Finland, and these clinics also ask patients to update PROs, such as the PREDSS and QOL measures, annually to provide insights into long-term changes. This may have led to the higher use of MyMS in these areas, and there are efforts to spread these practices nationwide via education and educational materials.

Successful treatment of MS relies on evidence-based medicine. High-quality health information is built from the knowledge and experience of HCPs combined with data from the lived experience of patients. The Finnish MS Register with MyMS is a clinical and patient interface, a unique e-health platform for this kind of data collection, and this is the first paper to report on it. There are numerous opportunities to further develop the collection and utilization of patient-generated data to improve the quality of care and increase patient participation. As more individuals with MS use the platform, the generalizability of the results increases, and research questions regarding the self-perceived symptomatology, disability, usage experiences, and other factors that are crucial in shared decision-making can be more efficiently addressed.

The Finnish MS Register includes an interface to promote patient contribution called MyMS, which includes validated patient-reported outcome measures (PROMs) on disease severity, symptoms, and impact, as well as quality of life.

Of the 21 Finnish counties with well-being services, 17 use the register and have the opportunity to collect PROMs. At present, although 90% of Finnish individuals with MS are on the register, only approximately 10% of them use MyMS.

MyMS offers a great opportunity to increase the use of PROMs because it is easily available to individuals as well as health care professionals.

 The study was financially supported by Janssen-Cilag Oy. The funder had no role in or influence on any aspect of the study, including data collection, data analysis, writing of the manuscript, and decision to publish. Preparation of this manuscript was funded in part by the Strategic Research Council within the Academy of Finland (funding No. 358415). Efforts to increase the use of the Finnish MS registry have received funding from Biogen Idec, Merck, Novartis, Sanofi Genzyme, Roche, Teva, and Business Finland.

 Päivi Hämäläinen and Matias Viitala are employees of StellarQ Ltd. The other authors of this manuscript do not declare any conflicts of interest related to this study.

MyMS: An Interface for Patient-Reported Outcomes for Finnish Individuals With Multiple Sclerosis

Sleep disturbances are common in individuals with multiple sclerosis. The objective of this systematic review was to determine effective behavioral interventions to improve their sleep.

Literature searches were performed in December 2021 in Ovid MEDLINE, Elsevier Embase, and Web of Science, along with hand searching for grey literature and cited references. Four reviewers independently reviewed titles and abstracts (2 reviewers for each article; n = 830) and the full-text articles (n = 81). Consensus for inclusion was achieved by a fifth reviewer. Thirty-seven articles were eligible for inclusion. Four reviewers extracted relevant data from each study (2 reviewers for each article) using a standard data extraction table. Consensus was achieved for completeness and accuracy of the data extraction table by a fifth reviewer. The same 4 reviewers conducted a quality appraisal of each article to assess the risk of bias and quality of the articles, and consensus was achieved by a fifth reviewer as needed. Descriptive data were used for types of interventions, sleep outcomes, results, and key components across interventions.

Overall, the cognitive behavioral therapy for insomnia, cognitive behavioral therapy/psychotherapy, and education/self-management support interventions reported positive improvements in sleep outcomes. Quality appraisal scores ranged from low to high, indicating potential for bias.

Variability in the intervention type, intervention dose, outcomes used, training/expertise of interventionist, specific sample, and study quality made it difficult to compare and synthesize results. Further research is necessary to demonstrate the efficacy of most of the interventions.

Nearly 1 million people in the United States are living with multiple sclerosis (MS), and disturbed sleep is a very common challenge in this population.

 Sleep problems are significantly more common in people with MS (~70%) than in the general population

; however, the incidence is likely higher because sleep disorders in individuals with MS are severely underdiagnosed.

Common contributors to sleep disturbances in people with MS include nocturia, muscle spasticity, depression, anxiety, and pain.

 Furthermore, neuropathology due to MS may have a direct physiological effect on circadian rhythm,

Amber Salter, PhD

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