Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis.

OBJECTIVE: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). METHODS: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. RESULTS: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. INTERPRETATION: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780-789.

Charting a global research strategy for progressive MS-An international progressive MS Alliance proposal.

BACKGROUND: Progressive forms of multiple sclerosis (MS) affect more than 1 million individuals globally. Recent approvals of ocrelizumab for primary progressive MS and siponimod for active secondary progressive MS have opened the therapeutic door, though results from early trials of neuroprotective agents have been mixed. The recent introduction of the term 'active' secondary progressive MS into the therapeutic lexicon has introduced potential confusion to disease description and thereby clinical management. OBJECTIVE: This paper reviews recent progress, highlights continued knowledge and proposes, on behalf of the International Progressive MS Alliance, a global research strategy for progressive MS. METHODS: Literature searches of PubMed between 2015 and May, 2021 were conducted using the search terms "progressive multiple sclerosis", "primary progressive multiple sclerosis", "secondary progressive MS". Proposed strategies were developed through a series of in-person and virtual meetings of the International Progressive MS Alliance Scientific Steering Committee. RESULTS: Sustaining and accelerating progress will require greater understanding of underlying mechanisms, identification of potential therapeutic targets, biomarker discovery and validation, and conduct of clinical trials with improved trial design. Encouraging developments in symptomatic and rehabilitative interventions are starting to address ongoing challenges experienced by people with progressive MS. CONCLUSION: We need to manage these challenges and realise the opportunities in the context of a global research strategy, which will improve quality of life for people with progressive MS.

The MULTI-ACT model: the path forward for participatory and anticipatory governance in health research and care.

The COVID-19 pandemic has unmasked even more clearly the need for research and care to form a unique and interdependent ecosystem, a concept which has emerged in recent years. In fact, to address urgent and unexpected missions such as "fighting all together the COVID-19 pandemic", the importance of multi-stakeholder collaboration, mission-oriented governance and flexibility has been demonstrated with great efficacy. This calls for a policy integration strategy and implementation of responsible research and innovation principles in health, promoting an effective cooperation between science and society towards a shared mission. This article describes the MULTI-ACT framework and discusses how its innovative approach, encompassing governance criteria, patient engagement and multidisciplinary impact assessment, represents a holistic management model for structuring responsible research and innovation participatory governance in brain conditions research.

Collective health research assessment: developing a tool to measure the impact of multistakeholder research initiatives.

BACKGROUND: The need to more collaboratively measure the impact of health research and to do so from multidimensional perspectives has been acknowledged. A scorecard was developed as part of the Collective Research Impact Framework (CRIF), to engage stakeholders in the assessment of the impacts of health research and innovations. The purpose of this study was to describe the developmental process of the MULTI-ACT Master Scorecard (MSC) and how it can be used as a workable tool for collectively assessing future responsible research and innovation measures. METHODS: An extensive review of the health research impact literature and of multistakeholder initiatives resulted in a database of 1556 impact indicators. The MSC was then cocreated by engaging key stakeholders and conducting semi-structured interviews of experts in the field. RESULTS: The MSC consists of five accountability dimensions: excellence, efficacy, economic, social and patient-reported outcomes. The tool contains 125 potential indicators, classified into 53 impact measurement aspects that are considered the most relevant topics for multistakeholder research and innovation initiatives when assessing their impact on the basis of their mission and their stakeholders' interests. The scorecard allows the strategic management of multistakeholder research initiatives to demonstrate their impact on people and society. The value of the tool is that it is comprehensive, customizable and easy to use. CONCLUSIONS: The MSC is an example of how the views of society can be taken into account when research impacts are assessed in a more sustainable and balanced way. The engagement of patients and other stakeholders is an integral part of the CRIF, facilitating collaborative decision-making in the design of policies and research agendas. In policy making, the collective approach allows the evaluation perspective to be extended to the needs of society and towards responsible research and innovation. Multidimensionality makes research and innovations more responsive to systemic challenges, and developing more equitable and sustainable health services.

Measuring outcomes that matter most to people with multiple sclerosis: the role of patient-reported outcomes.

PURPOSE OF REVIEW: Patient-reported outcome (PRO) represents a unique opportunity to measure the impact of health research, and care on outcomes that matter most to people with multiple sclerosis (PwMS). RECENT FINDINGS: How to incorporate PROs in MS clinical trials and, practice remains a matter of debate. The variety of measures available for use in MS has some benefits, but the lack of a set of standard measures has significant disadvantages. To help meeting the challenge, different PROs standard sets have been developed (PROMIS) for use across a broad range of chronic health conditions, and SymptoMScreen, specifically for MS. However, many of them were not co-created with PwMS and lacking understanding about what matters to patients. The newly proposed MS care unit model together with emerging initiatives such as iConquerMS and PROMOPROMS, are shaping new meaningful PROs. However, the uptake of PROMs in all settings can be effective only by a commonly held strategic agenda shared by all relevant stakeholders. SUMMARY: The newly born PRO Initiative for MS (PROMS) aims to develop a strategic agenda shared by all relevant stakeholders to help meeting the challenge of developing PRO measures that correspond to the needs of all stakeholders.

An "all-wheel drive" proposal to accelerate clinical research in common and rare neurological diseases.

The complex biology of neurological diseases calls for collaborative efforts that may increase the success rate of clinical research. Models have been proposed, but concrete actions remain insufficient. Based on recent considerations from basic science, from science of patient input and from an analysis of scientific resources in Italy, we here explain why our country may represent an appropriate environment for such actions. Furthermore, we sketch operational framework and business model to be applied in order to accelerate, in parallel, the development of therapies in common and rare diseases.

The Multiple Sclerosis Care Unit.

Treatment of multiple sclerosis (MS) has become increasingly multifaceted and comprises not only a variety of disease-modifying drugs with different mechanism of action but also a wide range of symptomatic therapies. Today, it is not possible for the family physician or even many general neurologists to master the current treatment algorithm, and this calls for the establishment of multidisciplinary MS Care Units. The core of the MS Care Unit would, in addition to MS neurologists and nurses, typically comprise neuropsychologists, clinical psychologists, physiotherapists, occupational therapists and secretaries, and will work together with a group of different specialists on formalized diagnostic workup procedures, protocols for initiation and follow-up of disease-modifying therapies. It is obvious that the terms of performance of different MS Care Units will vary across regions and need to be balanced with clinical practice according to local conditions. Although the main objective for establishment of MS Care Units will be to offer the single MS patient seamless and correct management of the disease to increase patient satisfaction and quality of life, it may even be cost-effective for the society by maintaining the working ability and reducing the costs of home help and custodial care by keeping people with MS resourceful.

Self-assessment reliability in multiple sclerosis: the role of socio-demographic, clinical, and quality of life aspects.

INTRODUCTION: Several multiple sclerosis studies matching self- and physician assessment of disease course and disability show moderate and high agreement respectively. However, the role played by socio-demographic, clinical, and quality of life (QoL) factors was not much investigated. The study aims at exploring how self-/physician agreement could depend on these variables. MATERIALS AND METHODS: Participants were asked to report own disease course and disability according to preset categories. Kappa-value and confidence interval (CI) for disease course and two-way random interclass correlation coefficient (ICC) and CI for disability were calculated to evaluate self-/physician agreement. Χ2 was applied to examine whether other factors (gender, age, education, civil status, disease duration, fatigue, quality of life) had systematic effects. RESULTS: Data analysis on 203 participants indicated fair agreement (Kappa-value = 0.30; 95% CI 0.23-0.38) and no dependency on the categories of each variable for disease course. Satisfactory correlation was found for disability (ICC = 0.74; 95% IC 0.67-0.80), good agreement was found for almost all variable categories, and significant differences were observed for education (better agreement for higher levels), disease duration, fatigue and QoL (better agreement for worse conditions). DISCUSSION: Results seem to suggest that higher education and worse clinical and QoL conditions could engage the patient in developing more disease awareness and realistic self-perception and self-evaluation.

Correction to: The Italian multiple sclerosis register.

Unfortunately in the original publication, the affiliation of the author Maria Pia Amato was incorrect. The author inadvertently missed out to include her second affiliation.

The Italian multiple sclerosis register.

The past decade has seen extraordinary increase in worldwide availability of and access to several large multiple sclerosis (MS) databases and registries. MS registries represent powerful tools to provide meaningful information on the burden, natural history, and long-term safety and effectiveness of treatments. Moreover, patients, physicians, industry, and policy makers have an active interest in real-world observational studies based on register data, as they have the potential to answer the questions that are most relevant to daily treatment decision-making. In 2014, the Italian MS Foundation, in collaboration with the Italian MS clinical centers, promoted and funded the creation of the Italian MS Register, a project in continuity with the existing Italian MS Database Network set up from 2001. Main objective of the Italian MS Register is to create an organized multicenter structure to collect data of all MS patients for better defining the disease epidemiology, improving quality of care, and promoting research projects in high-priority areas. The aim of this article is to present the current framework and network of the Italian MS register, including the methodology used to improve the quality of data collection and to facilitate the exchange of data and the collaboration among national and international groups.

Randomized controlled trial of a home-based palliative approach for people with severe multiple sclerosis.

BACKGROUND: Evidence on the efficacy of palliative care in persons with severe multiple sclerosis (MS) is scarce. OBJECTIVE: To assess the efficacy of a home-based palliative approach (HPA) for adults with severe MS and their carers. METHODS: Adults with severe MS-carer dyads were assigned (2:1 ratio) to either HPA or usual care (UC). At each center, a multi-professional team delivered the 6-month intervention. A blind examiner assessed dyads at baseline, 3 months, and 6 months. Primary outcome measures were Palliative care Outcome Scale-Symptoms-MS (POS-S-MS) and Schedule for the Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW, not assessed in severely cognitively compromised patients). RESULTS: Of 78 dyads randomized, 76 (50 HPA, 26 UC) were analyzed. Symptom burden (POS-S-MS) significantly reduced in HPA group compared to UC ( p = 0.047). Effect size was 0.20 at 3 months and 0.32 at 6 months, and statistical significance was borderline in per-protocol analysis ( p = 0.062). Changes in SEIQoL-DW index did not differ in the two groups, as changes in secondary patient and carer outcomes. CONCLUSION: HPA slightly reduced symptoms burden. We found no evidence of HPA efficacy on patient quality of life and on secondary outcomes.

Multiple sclerosis and rehabilitation: an overview of the different rehabilitation settings.

To date, a lack of accurate information about how the different rehabilitation settings are actually delivered to people with multiple sclerosis (PwMS) is still present. Here, we described how PwMS use the different rehabilitation settings in Italy. An observational retrospective study was designed and data collected through an anonymous questionnaire distributed attending MS clinical centers, rehabilitation units, or among PwMS affiliated to the Italian MS Society. We considered as settings: out-patient ambulatory therapy (OUT), hospitalized therapy (HOSP, in-patient and out-patient hospitalized therapy), and home-based therapy (HOME). One thousand six hundred eighty-six subjects at all disability levels were included in the analysis. A high number (53%, n = 890) did not receive rehabilitation care in the last 3 months before the interview. Main causes were probably due to organizational aspects and poor transports and road networks especially in Center and the Islands. The rehabilitation setting profile of the 796 subjects obtaining rehabilitation care consisted in 58.3% (n = 464) receiving only OUT setting, 9.4% (n = 75) only HOSP setting, and 21.7% (n = 173) only HOME setting. We observed a percentage of overlap among different rehabilitation settings: 3.9% (n = 31) OUT-HOME, 3.6% (n = 29) OUT-HOSP, 2.6% (n = 21) HOSP-HOME, and 0.4% (n = 3) OUT-HOME-HOSP. The physiotherapy was the treatment more common among different rehabilitation settings. Only in the in-patient hospitalized therapy setting, the patient received more frequently diversified treatment. Considering the results, the admission to rehabilitation care in Italy is still far from the standards outlined by the recent guidelines that hypothesize a multidisciplinary evaluation and a more individualized rehabilitation plan.

Multiple Sclerosis Questionnaire for Job Difficulties (MSQ-Job): definition of the cut-off score.

Multiple Sclerosis (MS) mainly affects people of working age. The Multiple Sclerosis Questionnaire for Job Difficulties (MSQ-Job) was designed to measure difficulties in work-related tasks. Our aim is to define cut-off score of MSQ-Job to identify potential critical situations that might require specific attention. A sample of patients with MS completed the MSQ-Job, WHODAS 2.0 and MSQOL-54 respectively for work difficulties, disability and health-related quality of life (HRQoL) evaluation. K-means Cluster Analysis was used to divide the sample in three groups on the basis of HRQoL and disability. ANOVA test was performed to compare the response pattern between these groups. The cut-off score was defined using the receiver operating characteristic (ROC) curve analyses for MSQ-Job total and count of MSQ-Job items scores ≥3: a score value corresponding to the maximum of the sensitivity-to-specificity ratio was chosen as the cut-off. Out of 180 patients enrolled, twenty were clustered in the higher severity group. The area under the ROC curve was 0.845 for the MSQ-Job total and 0.859 for the count of MSQ-Job items scores ≥3 while the cut-off score was 15.8 for MSQ-Job total and 8 for count of items scored ≥3. We recommend the use of MSQ-Job with this calculation as cut-off for identifying critical situations, e.g. in vocational rehabilitation services, where work-related difficulties have a significant impact in terms of lower quality of life and higher disability.

Adaptive vs. non-adaptive cognitive training by means of a personalized App: a randomized trial in people with multiple sclerosis.

BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS), but the definition of the best cognitive rehabilitation tools and features is still an open issue among researchers. The aims of the present study were to evaluate the effectiveness of COGNI-TRAcK (a customized application software delivering personalized working memory-based exercises) on cognitively impaired people with MS and to investigate the effects of an adaptive vs. a non-adaptive cognitive training administered by means of COGNI-TRAcK. METHODS: Twenty eight patients (20 women, age 47.5 ± 9.3 years, Expanded Disability Status Scale score 3.8 ± 1.9) were randomized in two homogeneous groups, both performing a 8-week home-based cognitive rehabilitation treatment by means of COGNI-TRAcK. The study group (ADAPT-gr) underwent an adaptive training given by the automatic adjustment of tasks difficulty to the subjects' performance, whilst the control group (CONST-gr) was trained at constant difficulty levels. Before and after the treatment, patients' cognitive status was assessed using a gold standard neuropsychological evaluation. Moreover, the mostly affected cognitive domains in MS (i.e., attention, concentration and information processing speed) were also assessed 6 months after the end of the treatment. RESULTS: The analysis of variance showed a significant Group*Time interaction in six out of ten tests of the cognitive evaluation. Post-hoc analysis revealed a significant improvement between the performances before and after the intervention only in the ADAPT-gr in tests evaluating verbal memory acquisition (p <0.05) and delayed recall (p = 0.001), verbal fluency (p = 0.01), sustained attention, concentration and information processing speed (p < 0.01). This last effect was maintained also after 6 months (p < 0.05). CONCLUSIONS: We concluded that COGNI-TRAcK represents a suitable tool to administer a personalized training to cognitively impaired subjects and that an adaptive working load is a crucial feature determining the effectiveness of cognitive treatment, allowing transfer effects to several cognitive domains and long-term maintenance of results.

Workers with disability: the case of multiple sclerosis.

The impact of the multiple sclerosis (MS) on the individual's ability to work is important especially because the onset of the disease occurs mainly between 20 and 30 years of age. This study evaluated different factors associated with job maintenance using a questionnaire that defined what factors are considered obstacle or help in work management. A cross-sectional study of people with MS was carried out in Italy. A total of 1016 individuals with MS were enrolled in the study. Our results showed that negative item related to job maintenance as 'attitudes of other in the workplace' was associated with a lower likelihood of being employed (OR 0.65, 95% CI 0.57-0.76), while 'your attitudes toward work' (OR 1.37, 95% CI 1.19-1.59), 'attitudes of other in the workplace' (OR 1.41, 95% CI 1.17-1.69) and 'personal considerations' (OR 1.54, 95% CI 1.23-1.93), positive items related to job maintenance, were associated with a higher likelihood of being employed. In addition, a poor quality of life and severity disease as well same demographic characteristics (i.e. to be resident in South Italy or in the Islands, living in own original family, have lower educational level) inhibited significantly the job maintenance together with a heavy job and a fixed-term contract. In conclusion, a complex set of variables contribute to the barriers faced by PwMS who are employed suggesting that different stakeholders may play an important role in difficult management of the work for people with MS.

Economic impact of multiple sclerosis in Italy: focus on rehabilitation costs.

The study estimates the cost of multiple sclerosis (MS) in Italy quantifying the impact of the rehabilitation on cost of illness. Patients with MS were enrolled at MS clinical centres, in rehabilitation units and among members with MS of the Italian MS Society across the Italy. The MS costs were captured with a questionnaire and were estimated taking into account both healthcare and non-healthcare costs as well as the productivity losses. Mean total annual costs per patients were €37,948, increasing for different disease severity: from €22,750 at an EDSS score of 0-3 to €63,047 at an EDSS score equal to or more than 7. €3,418 was due to rehabilitation (about 26.7% of direct healthcare costs) and of these 44% was attributable to admission to rehabilitation. The multivariate analysis showed a consistent trend toward increased total cost with progressive severity of MS, with presence of relapses, while the total cost decreases with a better quality of life. The burden increases as the MS becomes more severe and with relapse occurrence, moreover we observed high costs due to admission to rehabilitation suggesting that different rehabilitation setting might be considered to reduce the financial burden and increase the quality of life for person with MS.

Unmet care needs of people with a neurological chronic disease: a cross-sectional study in Italy on Multiple Sclerosis.

BACKGROUND: Community-based studies are required to accurately describe the supportive services needed by people with multiple sclerosis (MS). METHODS: A total of 1205 people with MS participated in a cross-sectional study evaluating their unmet health and social care needs through a questionnaire collecting information used in the study. It was specifically developed by a multi-disciplinary team. RESULTS: Overall, 79% of the responders declared at least one health or social care needs. The most prevalent health care need was the psychological support (27.5%), whereas the transport was the social care need more frequent (over 41%) in our sample. The multivariate analysis highlighted that unmet health care needs depended mainly on clinical factors such as disease stage, influenced by disease duration, and disability degree, whereas the social care needs were related to both clinical and socio-demographic factors. CONCLUSION: These findings suggest that MS needs significantly change over time during the disease development and to find the best way to personalize PwMS management is crucial. Moreover, more public funding directed at improving the health-related quality of life of people with MS is needed. For this reason, we think that these results will provide important information and baseline data on how to build the national service strategies thereby making healthcare planning more efficient.

Funding Medical Research Projects: Taking into Account Referees' Severity and Consistency through Many-Faceted Rasch Modeling of Projects' Scores.

The funding policy of research projects often relies on scores assigned by a panel of experts (referees). The non-linear nature of raw scores and the severity and inconsistency of individual raters may generate unfair numeric project rankings. Rasch measurement (many-facets version, MFRM) provides a valid alternative to scoring. MFRM was applied to the scores achieved by 75 research projects on multiple sclerosis sent in response to a previous annual call by FISM-Italian Foundation for Multiple Sclerosis. This allowed to simulate, a posteriori, the impact of MFRM on the funding scenario. The applications were each scored by 2 to 4 independent referees (total = 131) on a 10-item, 0-3 rating scale called FISM-ProQual-P. The rotation plan assured "connection" of all pairs of projects through at least 1 shared referee.The questionnaire fulfilled satisfactorily the stringent criteria of Rasch measurement for psychometric quality (unidimensionality, reliability and data-model fit). Arbitrarily, 2 acceptability thresholds were set at a raw score of 21/30 and at the equivalent Rasch measure of 61.5/100, respectively. When the cut-off was switched from score to measure 8 out of 18 acceptable projects had to be rejected, while 15 rejected projects became eligible for funding. Some referees, of various severity, were grossly inconsistent (z-std fit indexes less than -1.9 or greater than 1.9). The FISM-ProQual-P questionnaire seems a valid and reliable scale. MFRM may help the decision-making process for allocating funds to MS research projects but also in other fields. In repeated assessment exercises it can help the selection of reliable referees. Their severity can be steadily calibrated, thus obviating the need to connect them with other referees assessing the same projects.

Accelerated axonal loss following acute CNS demyelination in mice lacking protein tyrosine phosphatase receptor type Z.

Protein tyrosine phosphatase receptor type Z (Ptprz) is widely expressed in the mammalian central nervous system and has been suggested to regulate oligodendrocyte survival and differentiation. We investigated the role of Ptprz in oligodendrocyte remyelination after acute, toxin-induced demyelination in Ptprz null mice. We found neither obvious impairment in the recruitment of oligodendrocyte precursor cells, astrocytes, or reactive microglia/macrophage to lesions nor a failure for oligodendrocyte precursor cells to differentiate and remyelinate axons at the lesions. However, we observed an unexpected increase in the number of dystrophic axons by 3 days after demyelination, followed by prominent Wallerian degeneration by 21 days in the Ptprz-deficient mice. Moreover, quantitative gait analysis revealed a deficit of locomotor behavior in the mutant mice, suggesting increased vulnerability to axonal injury. We propose that Ptprz is necessary to maintain central nervous system axonal integrity in a demyelinating environment and may be an important target of axonal protection in inflammatory demyelinating diseases, such as multiple sclerosis and periventricular leukomalacia.