Antibody response to SARS-CoV-2 vaccines in patients with relapsing multiple sclerosis treated with evobrutinib: A Bruton's tyrosine kinase inhibitor.

BACKGROUND: Evobrutinib is an oral, central nervous system (CNS)-penetrant and highly selective covalent Bruton's tyrosine kinase inhibitor under clinical development for patients with relapsing multiple sclerosis (RMS). OBJECTIVE: To investigate the effect of evobrutinib on immune responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinated patients with RMS from a Phase II trial (NCT02975349). METHODS: A post hoc analysis of patients with RMS who received evobrutinib 75 mg twice daily and SARS-CoV-2 vaccines during the open-label extension (n = 45) was conducted. Immunoglobulin (Ig)G anti-S1/S2-specific SARS-CoV-2 antibodies were measured using an indirect chemiluminescence immunoassay. RESULTS: In the vaccinated subgroup, mean/minimum evobrutinib exposure pre-vaccination was 105.2/88.7 weeks. In total, 43 of 45 patients developed/increased S1/S2 IgG antibody levels post-vaccination; one patient's antibody response remained negative post-vaccination and the other had antibody levels above the upper limit of detection, both pre- and post-vaccination. Most patients (n = 36/45), regardless of pre-vaccination serostatus, had a 10-100-fold increase of antibody levels pre- to post-vaccination. Antibody levels post-booster were higher versus post-vaccination. CONCLUSION: These results suggest evobrutinib, an investigational drug with therapeutic potential for patients with RMS, acts as an immunomodulator, that is, it inhibits aberrant immune cell responses in patients with RMS, while responsiveness to foreign de novo and recall antigens is maintained.

Improvements in quality of life over 2 years with cladribine tablets in people with relapsing multiple sclerosis: The CLARIFY-MS study.

BACKGROUND: Multiple sclerosis (MS) negatively affects health-related quality of life (HRQoL). OBJECTIVE: To evaluate HRQoL in people with highly active relapsing MS treated with cladribine tablets (CladT; 3.5 mg/kg cumulative dose over 2 years) in CLARIFY-MS. METHODS: Changes in the MS quality of life (MSQoL)-54 scores were analysed using a repeated mixed-effects linear model. Subgroup analyses were performed for participants who were pretreatment-naïve and those pretreated with disease-modifying therapies (DMTs) before initiating CladT. Safety and tolerability of CladT were also assessed. RESULTS: MSQoL-54 physical (mean change = 4.86; 95% confidence interval (CI) = 3.18, 6.53) and mental health (4.80; 95% CI = 3.13, 6.46) composite scores (primary endpoints) showed significant improvement at Month 24 versus Baseline (p < 0.0001). Changes in the MSQoL-54 scores were consistent across the pretreatment-naïve and DMT-pretreated subgroups. No new severe or opportunistic infections occurred. Most post-baseline lymphopenia events were Grade 1-2 in severity. Transient Grade-3 lymphopenia was observed in 19.7% (95/482) of participants. Grade-4 lymphopenia was not observed. CONCLUSIONS: CladT treatment significantly improved the mean MSQoL-54 physical and mental health composite scores over 2 years. CladT efficacy in HRQoL, relapse rates and Expanded Disability Status Scale scores demonstrates its multidimensional effects in MS treatment.

Reduction in grey matter atrophy in patients with relapsing multiple sclerosis following treatment with cladribine tablets.

BACKGROUND AND PURPOSE: Measures of atrophy in the whole brain can be used to reliably assess treatment effect in clinical trials of patients with multiple sclerosis (MS). Trials assessing the effect of treatment on grey matter (GM) and white matter (WM) atrophy are very informative, but hindered by technical limitations. This study aimed to measure GM and WM volume changes, using a robust longitudinal method, in patients with relapsing MS randomized to cladribine tablets 3.5 mg/kg or placebo in the CLARITY study. METHODS: We analysed T1-weighted magnetic resonance sequences using SIENA-XL, from 0 to 6 months (cladribine, n = 267; placebo, n = 265) and 6 to 24 months (cladribine, n = 184; placebo, n = 186). Mean percentage GM and WM volume changes (PGMVC and PWMVC) were compared using a mixed-effect model. RESULTS: More GM and WM volume loss was found in patients taking cladribine versus those taking placebo in the first 6 months of treatment (PGMVC: cladribine: -0.53 vs. placebo: -0.25 [p = 0.045]; PWMVC: cladribine: -0.49 vs. placebo: -0.34 [p = 0.137]), probably due to pseudoatrophy. However, over the period 6 to 24 months, GM volume loss was significantly lower in patients on cladribine than in those on placebo (PGMVC: cladribine: -0.90 vs. placebo: -1.27 [p = 0.026]). In this period, volume changes in WM were similar in the two treatment arms (p = 0.52). CONCLUSIONS: After a short period of pseudoatrophy, treatment with cladribine 3.5 mg/kg significantly reduced GM atrophy in comparison with placebo. This supports the relevance of GM damage in MS and may have important implications for physical and cognitive disability progression.

Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: The CLARITY and CLARITY Extension studies.

BACKGROUND: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study of patients with relapsing-remitting multiple sclerosis, treatment with cladribine tablets 3.5 mg/kg (CladT) significantly reduced the annualised relapse rate (ARR) versus placebo; this effect was sustained in CLARITY Extension, without further treatment. OBJECTIVE: To assess the frequency and severity of relapses in patients treated with CladT versus placebo in CLARITY over 2 years and evaluate the durability of effect in patients who received no further treatment for 2 years in CLARITY Extension. METHODS: In this post hoc analysis, ARRs were calculated for qualifying and all relapses, and qualifying and all severe relapses (i.e. requiring steroid treatment or leading to hospitalisation) in patients treated with CladT (n = 433) and placebo (n = 437) in CLARITY, and those from the CladT group who received placebo in CLARITY Extension (n = 98). RESULTS: At Month 6, Year 1 and Year 2, patients receiving CladT had a significantly lower risk of qualifying or all relapses (all p < 0.0001), and qualifying or all severe relapses (all p < 0.005), compared with placebo. This effect was sustained in CLARITY Extension without further treatment. CONCLUSION: The results show durable efficacy of cladribine tablets 3.5 mg/kg for reducing frequency and severity of relapses in patients with relapsing-remitting multiple sclerosis.CLARITY: NCT00213135; CLARITY Extension: NCT00641537.

Prevalence of disability improvement in relapsing-remitting multiple sclerosis patients treated with cladribine tablets.

BACKGROUND AND PURPOSE: The aim was to show the application of the prevalence estimator of Expanded Disability Status Scale (EDSS) improvement over time in patients treated with cladribine tablets in the phase III CLARITY/CLARITY extension trials. METHODS: Relapsing-remitting multiple sclerosis patients who entered the CLARITY extension study were evaluated. Patients originally randomized in CLARITY to cladribine tablets 3.5 mg/kg and placebo in CLARITY extension (early cladribine [EC]) were compared to patients originally randomized to placebo and then assigned to cladribine tablets 3.5 mg/kg (delayed cladribine [DC]). The EC group was compared to the DC group on the prevalence of EDSS improvement over time and on the cumulative incidence of EDSS improvement. Prevalence of improvement was assessed by a new approach based on the difference of Kaplan-Meier estimators, whilst the incidence of improvement was assessed by standard Kaplan-Meier curves. RESULTS: A total of 98 patients in the EC group and 244 patients in the DC group were compared. Patients in the EC group showed a significantly higher (p = 0.011) prevalence of improvement at year 2 (EC 21.3%, 95% confidence interval [CI] 13.6-29.3; DC 8.9%, 95% CI 5.5-12.8) and at year 5 (EC 15.7%, 95% CI 8.2-23.7; DC 8.3%, 95% CI 4.5-12.4). The cumulative incidence of improvement was also significantly different (hazard ratio 1.82, 95% CI 1.13-2.94, p = 0.013). CONCLUSIONS: Assessment of the prevalence of EDSS improvement is an alternative outcome to assess if a treatment induces and maintains an improvement over the long term. This estimator was found to be more powerful than the cumulative incidence of improvement to detect a treatment effect of cladribine versus placebo over 5 years.

Summary of Research: What Is the True Impact of Cognitive Impairment for People Living with Multiple Sclerosis? A Commentary of Symposium Discussions at the 2020 European Charcot Foundation.

Cognitive symptoms affect disease management and activities of daily living for people living with multiple sclerosis (MS). This summary of research article summarises previously published discussions ('What is the true impact of cognitive impairment for people living with multiple sclerosis? A commentary of symposium discussions at the 2020 European Charcot Foundation') from the 2020 European Charcot Foundation meeting between a patient expert living with MS, a neuropsychologist and a neurologist about the impact of cognitive impairment on people living with MS. These discussions highlighted that cognitive impairment may be under-prioritised in MS care and has a substantial impact on the daily lives of people living with MS. To address this, the panel recommended improved awareness about impaired cognition in MS, improved communication between people living with MS and healthcare professionals, and routine cognition screening. This will help improve management of cognitive symptoms to maximise the quality of life of people living with MS.

Cognitive impairment and its impact on employment: A qualitative interview-based study involving healthcare professionals and people living with multiple sclerosis.

BACKGROUND: Cognitive impairment can considerably impact the work life of people who have multiple sclerosis (MS). Cognitive symptoms are associated with an increased likelihood of unemployment, changes in employment and decreased working hours. This qualitative interview-based study aims to gather real-word experiences and perspectives from both people living with MS and healthcare professionals, to explore how cognitive symptoms are experienced in the workplace, how their impact is addressed, and what can be done to support people in managing and minimizing this impact on employment. METHODS: Semi-structured, one-to-one interviews were conducted with people living with MS who experience cognitive symptoms, and with healthcare professionals working in MS care. Participants were recruited from a healthcare market research agency based in the United States. The data obtained from the interviews were subsequently analysed using a Grounded Theory method, in order to identify the core themes that form the basis of this paper. RESULTS: A total of 20 participants (n = 10 people living with MS; n = 10 healthcare professionals) from the United States were interviewed. Overall, 9 themes were identified from the raw data, which were grouped into three core themes describing the perspectives and experiences reported by both people living with MS and healthcare professionals: (1) The implications of cognitive symptoms on work; (2) Challenges in addressing cognitive impairment and its impact on work in MS care; (3) Strategies and support for managing the impact of cognitive symptoms. CONCLUSION: The real-world insights of PwMS and HCPs gained from this qualitative study show that a multi-faceted approach to addressing cognitive impairment and its impact on the employment of PwMS is required. Workplace adjustments can range from self-implemented changes to changes put in place by employers to accommodate the various ways in which cognitive symptoms may impact a person's work. This study provides valuable information on how people living with MS can be affected by cognitive symptoms in the context of their employment; furthermore, that preparing early when possible and maintaining a proactive approach to managing their impacts on work are important for maintaining a good quality of life.

What Is the True Impact of Cognitive Impairment for People Living with Multiple Sclerosis? A Commentary of Symposium Discussions at the 2020 European Charcot Foundation.

Multiple sclerosis (MS) is a chronic, neurodegenerative, inflammatory condition usually associated with physical disability. Clinical care has been skewed toward the physical manifestations of the disease, yet a range of silent symptoms occurs including the cognitive aspects of MS. In a 2018 meeting of MS in the 21st Century (MS21), an international steering committee comprising both specialists and patient experts recognised that the 'invisible symptoms' of MS pose a significant challenge to patient engagement. These findings prompted the European Charcot Foundation (ECF) MS21 symposium (2020), where a panel consisting of two leading MS clinicians and an MS patient expert (who were all members of the MS21 steering group) gathered to discuss the impact of cognitive impairment on the everyday lives of people with MS.The perspectives and experiences of the panellists are summarised in this paper. The key points raised were that (1) the cognitive manifestations of MS are under-recognised and have consequently been undermanaged from a clinical perspective and (2) cognitive impairment due to MS has a significant impact upon daily living and patient quality of life. During discussions about how these challenges can be addressed, the panel advocated for an improvement in education about cognitive symptoms for people living with MS and healthcare professionals (HCPs) to raise awareness about this aspect of MS. Furthermore, the panel emphasised the importance of open and proactive communication between HCPs and their patients with MS about cognitive symptoms to reduce the stigma attached to these symptoms. In the opinion of the panel, future clinical trials which include cognitive outcomes as key endpoints are needed. Reflecting this point, cognitive impairment in MS care also needs to be treated as an important disease symptom, as is done with physical symptoms of the disease. Implementing early and routine cognition screening and promoting measures for protecting cognition to people living with MS, such as cognitive rehabilitation and a 'brain-healthy' lifestyle, are actions which can drive forward the recognition of cognitive impairment as a care priority.If prioritised as highly as physical disability in both the MS care and clinical drug development setting, and proactively discussed in conversations between HCPs and patients with MS, the 'invisibility' of cognitive impairment in MS can be lifted and a better quality of life can be promoted for people living with MS.

Multiple sclerosis is a long-term condition which affects the brain and nervous system. Multiple sclerosis care has often focused more on the physical aspects of the disease than its mental challenges. Examples of mental challenges are brain fog, which can make it hard to organise thoughts, and memory problems. In 2020, the Multiple Sclerosis in the 21st Century group held a meeting at a medical conference called the European Charcot Foundation. In this conference, a patient expert living with multiple sclerosis, together with a neuropsychologist and neurologist both specialising in multiple sclerosis, discussed its mental symptoms and why they are not always recognised and addressed by people with multiple sclerosis and their healthcare teams. The group emphasised that these symptoms can considerably affect the day-to-day lives of people who experience them, stressing that this is a key reason why mental symptoms need to be better prioritised in care. The group advocated for early and frequent cognition testing to be a part of the standard care approach, as is the case with physical symptoms. They also urged healthcare professionals to promote a 'brain-healthy' lifestyle to their patients with multiple sclerosis and to encourage participation in cognitive rehabilitation programmes to maintain their mental abilities in the long run. Finally, the group discussed that more drug development studies that specifically assess how a treatment can reduce mental symptoms are needed: in this way, research and healthcare approaches can better prioritise mental symptoms.

Summary of Research: Caregiver Involvement in MS: Duty or Disruption?

This Summary of Research summarizes a previously published discussion between people with multiple sclerosis (PwMS) and their caregivers and healthcare professionals (HCPs) about how to include caregivers in consultations and decisions about multiple sclerosis (MS) care. The aim of the discussion was to help HCPs to understand differences in these relationships so they can adapt the style of consultations to support everyone.

Assessing the duration of EDSS improvement after a therapy start: A novel approach applied to the long-term extension of the PRISMS study.

BACKGROUND: In a chronic and progressive disease such as multiple sclerosis (MS), the improvement on Expanded Disability Status Scale (EDSS) can be a transient event. Therefore, estimating the prevalence of disability improvement over time, accounting both for improvement incidence and duration, is of interest. The aim of this study was to show the application of a simple estimator for the proportion of patients with sustained improvement over time using data from the long-term extension of the PRISMS trial. METHODS: A total of 534 relapsing-remitting MS (RRMS) patients from the PRISMS trial were included. Patients with a baseline EDSS of 0 were excluded. Patients were randomized to placebo (n = 178), subcutaneous interferon beta-1a (sc IFN ß-1a) 22 µg (n = 181) or sc IFN ß-1a 44 µg (n = 175). At Year 2, patients receiving placebo were re-randomized to sc IFN ß-1a 22 µg or 44 µg (delayed sc IFN ß-1a) while patients receiving sc IFN ß-1a 22 µg or 44 µg continued their initial regimen. Patients were followed up for over 7 years post-randomization. Disability improvement was defined as a 1-point decrease in EDSS from baseline confirmed at 6 months. Prevalence of improvement was estimated as difference of Kaplan-Meier (KM) estimators while the cumulative incidence of improvement was calculated using the standard KM curves. RESULTS: No significant differences in cumulative incidence of EDSS improvement at 3 years between delayed sc IFN ß-1a (20.3%) and sc IFN ß-1a 22 µg (20.8%; p = 0.49) or 44 µg (21.3%; p = 0.33). When taking duration of improvement into account, the proportion of patients showing an improved condition after 3 years was 10.1% with delayed sc IFN ß-1a, 11.3% with sc IFN ß-1a 22 µg (p = 0.17) and 15.4% with sc IFN ß-1a 44 µg (p = 0.037) that was substantially maintained over the long term. CONCLUSIONS: With the use of this new statistical methodology, it is possible to estimate the time to improvement as well as the duration of improvement, information that is better suited to describing a non-final outcome like disability improvement. In this case, early sc IFN ß-1a 44 µg initiation had a greater proportion of patients with a sustained disability improvement over a long period of follow-up as compared to patients who had initially been randomized to placebo. In contrast, no significant differences on the cumulative incidence of improvement were observed.

Summary of Research: Collaboration Between Healthcare Professionals and People with Multiple Sclerosis to Develop Communication Tools to Improve the Standard of Multiple Sclerosis Care.

This is a summary of a previously published paper: Joint Healthcare Professional and Patient Development of Communication Tools to Improve the Standard of MS Care. It describes a collaboration between people with multiple sclerosis (PwMS) and healthcare professionals (HCPs) to identify challenges in multiple sclerosis (MS) care and design tools to improve communication during consultations.

Identification of an agrin mutation that causes congenital myasthenia and affects synapse function.

We report the case of a congenital myasthenic syndrome due to a mutation in AGRN, the gene encoding agrin, an extracellular matrix molecule released by the nerve and critical for formation of the neuromuscular junction. Gene analysis identified a homozygous missense mutation, c.5125G>C, leading to the p.Gly1709Arg variant. The muscle-biopsy specimen showed a major disorganization of the neuromuscular junction, including changes in the nerve-terminal cytoskeleton and fragmentation of the synaptic gutters. Experiments performed in nonmuscle cells or in cultured C2C12 myotubes and using recombinant mini-agrin for the mutated and the wild-type forms showed that the mutated form did not impair the activation of MuSK or change the total number of induced acetylcholine receptor aggregates. A solid-phase assay using the dystrophin glycoprotein complex showed that the mutation did not affect the binding of agrin to alpha-dystroglycan. Injection of wild-type or mutated agrin into rat soleus muscle induced the formation of nonsynaptic acetylcholine receptor clusters, but the mutant protein specifically destabilized the endogenous neuromuscular junctions. Importantly, the changes observed in rat muscle injected with mutant agrin recapitulated the pre- and post-synaptic modifications observed in the patient. These results indicate that the mutation does not interfere with the ability of agrin to induce postsynaptic structures but that it dramatically perturbs the maintenance of the neuromuscular junction.

Caregiver Involvement in MS: Duty or Disruption?

Multiple sclerosis (MS) is a complex condition with numerous physical, cognitive and emotional symptoms. These may necessitate significant, permanent lifestyle changes for people with multiple sclerosis (PwMS) and their caregivers and families, meaning it is important in contemporary neurological practice to consider including families and/or caregivers in the management of MS. However, existing evidence suggests that family involvement is not always beneficial; for example, it can exert either a strong positive or negative influence on the ability of PwMS to achieve optimal outcomes from their treatment and disease management. This paper, based on a live debate between neurologists and PwMS, examines the current perceptions on constructive involvement of families and caregivers in consultations for and management of MS, and reveals several areas where additional studies are warranted. Shared decision-making in MS has historically been a collaboration solely between healthcare professionals (HCPs) and PwMS, but PwMS are now more frequently being accompanied to appointments by a support person. This paper encourages HCPs to understand the dynamics between PwMS and their support person, and to individualize consultations and information accordingly. Family and caregiver involvement in the provision of care for PwMS needs to be for the benefit of, and at the discretion of, the PwMS. Support for families of PwMS, although important, may be more effectively and appropriately delivered through other channels outside of the clinical setting. Educating HCPs on the current patient experience to enable them to provide improved personalized care will ensure a mutualistic, patient-centred relationship with PwMS, which will help to optimize outcomes. Communication tools may also facilitate these interactions.

Multiple sclerosis (MS) is a highly variable condition. The uncertainty this brings can affect the mental well-being of the entire family of someone living with MS. Additionally, people with MS may need help administering and remembering to use medicines, and require changes to the way they live their life (e.g. employment decisions, home adjustments and care), which can also disrupt the family's lifestyle. The family undoubtedly needs to be involved in certain decisions, such as family planning, or when caring for very young or old people with MS. However, extensive family involvement may not always be a good thing for all people with MS. Therefore, it is the responsibility of healthcare professionals to understand the pivotal role of the caregiver and seek appropriate opportunities to engage with family and support persons on a case-by-case basis. To highlight the importance of family members in the management of MS, an international group of expert neurologists and people with MS discussed the best ways to involve families in consultations and decision-making, without disrupting care or undermining the independence of the people with MS. The group stresses that a family's involvement in the provision of care needs to be for the benefit of the people with MS and that many factors can influence whether family involvement is perceived positively or negatively by the people with MS. Support for the family is important; however, it may be more appropriately delivered outside the healthcare professional consultation, and instead provided by a patient or caregiver organization.

Relapses in people with multiple sclerosis treated with cladribine tablets followed for up to 5 years: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article originally published in the Multiple Sclerosis Journal. The article presents the results from the CLARITY and CLARITY Extension studies, which looked at how well cladribine tablets work in treating people with multiple sclerosis (shortened to MS). Cladribine tablets are a medication approved for treating relapsing forms of MS. This study looked at how treatment with cladribine tablets affects the frequency and severity of relapses in people with MS. A relapse is when new symptoms develop or old symptoms return or get worse after a period of stability or improvement. WHAT HAPPENED IN THE STUDIES?: In the CLARITY study, 870 people received either cladribine tablets (3.5 mg/kg, the approved dose) or placebo (a dummy pill). After the CLARITY study ended, some participants who received cladribine tablets chose to take part in a second study called the CLARITY Extension study. Of these participants, 98 were given placebo for 2 more years following an interval period of up to 10 months between participating in each study. WHAT WERE THE RESULTS?: People with MS who were treated with cladribine tablets for 2 years in the CLARITY study had lower risks of any relapse compared with those given placebo. Participants taking placebo (after cladribine tablets) in the CLARITY Extension study experienced these same benefits, which continued for up to 3 more years after having received cladribine tablets in the CLARITY study. WHAT DO THE RESULTS MEAN?: Researchers concluded the recommended 2-year dosing of cladribine tablets may reduce the number and severity of relapses in people with MS for up to 5 years. Clinical Trial Registration: NCT00213135 (ClinicalTrials.gov) Clinical Trial Registration: NCT00641537 (ClinicalTrials.gov).

Treatment satisfaction, safety, and tolerability of cladribine tablets in patients with highly active relapsing multiple sclerosis: CLARIFY-MS study 6-month interim analysis.

Background Multiple sclerosis (MS) is a chronic disabling disease that is associated with negative effects on health-related quality of life (HRQoL) due to reduced physical and psychosocial functioning. Cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years) have been approved for the treatment of adult patients with highly active relapsing multiple sclerosis (RMS). The ongoing CLARIFY-MS study (NCT03369665; EudraCT number: 2017-002632-17) aims to assess the effect of cladribine tablets 3.5 mg/kg on HRQoL of patients with highly active RMS. Objective To report on the design of the CLARIFY-MS study, baseline patient characteristics, and results of a pre-planned interim analysis focusing on treatment satisfaction, safety, and tolerability that includes all data reported till 6 months after start of treatment. Methods The CLARIFY-MS study is a 2-year, open-label, single-arm, prospective, multicenter, phase IV study. Eligible patients with highly active RMS were assigned to receive cladribine tablets 3.5 mg/kg over 2 years. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM, v1.4; scale range from 0 to 100, higher values indicating higher satisfaction). Safety assessments, including occurrence of treatment-emergent adverse events (TEAEs; any adverse event reported after drug administration), serious adverse events (SAEs), and lymphocyte counts, were summarized descriptively. Results A total of 482 patients from 85 sites in Europe were treated with cladribine tablets. Mean patient age was 37.4 years, 338 (70.1%) were women, median EDSS was 2.5, and 345 (71.6%) were prior users of disease-modifying therapy (DMT). During the first 6 months after the start of treatment, and before reaching the full dose of cladribine tablets, mean TSQM global satisfaction score for the overall population was 70.4 (standard deviation, ± 18.48). The side effects score was 91.9 (± 17.68), convenience scored 86.6 (± 13.57), and effectiveness was 65.8 (± 21.14). A total of 275 patients (57.1%) reported at least one TEAE and 9 patients (1.9%) had a SAE. The majority of observed lymphopenia cases were of grade 1 or 2; 33 (6.8%) of the total study cohort had grade 3 lymphopenia, and no grade 4 lymphopenia was reported. Conclusion Patients reported high treatment satisfaction (TSQM) with cladribine tablets in this pre-planned interim analysis at 6 months. Few serious, and no unexpected, adverse events were reported, and there were no instances of grade 4 lymphopenia over the first 6 months. These preliminary data indicate good tolerability and convenience of administration of cladribine tablets in patients with highly active RMS.

Disease Progression in Multiple Sclerosis: A Literature Review Exploring Patient Perspectives.

PURPOSE: Multiple sclerosis (MS) prognosis is often uncertain. This literature review considers patients' understanding of, and perspectives on, MS progression to better comprehend the unmet needs of people with MS (PwMS), in order to improve treatment adherence and quality of life (QoL). METHODS: Literature searches for peer-reviewed papers concerning patient perspectives on the progression of MS and comparable conditions, published between January 2000 and January 2020, were conducted. RESULTS: Little qualitative evidence exists that examines PwMS' perspectives on MS progression. The understanding and meaning ascribed to terms such as "disease progression" vary. Some PwMS find disease labels stigmatizing, confusing, and disconnected from reality. The lack of a clear definition of progression and discrepancies between PwMS and healthcare professional (HCP) perspectives may contribute to misunderstanding and poor communication. Patient descriptions of progression and relapses include symptoms in addition to those evaluated by standard severity and disability measures. Compared with HCPs, PwMS are still focused on relapse prevention but place higher priority on QoL and ascribe different relative importance to the causes of poor adherence to treatment plans. PwMS want to discuss progression and likely prognosis. Such communication needs to be personalized and delivered with sensitivity, at an appropriate time. Poor treatment adherence may arise from a lack of understanding and poor communication, particularly around treatment goals. The few studies that directly considered patient perspectives on the progression of comparable conditions supported and extended the perspectives of PwMS. Lack of adequate communication by HCPs was the most common theme. CONCLUSION: Patient perspectives on disease progression in MS and other chronic progressive conditions are under-investigated and under-reported. The limited evidence available highlights the importance of providing adequate information and effective HCP communication. While further studies are needed, the current evidence base offers information and insights that may help HCPs to enhance patient care, well-being, and treatment adherence.

Knowledge Is Power, but Is Ignorance Bliss? Optimising Conversations About Disease Progression in Multiple Sclerosis.

Communication about multiple sclerosis (MS) disease progression between healthcare professionals (HCPs) and people with MS (PwMS) has historically been considered difficult, and attention to improving it has been neglected. However, a growing number of studies have shown that this is a key area to get right, since negative experiences can affect patient satisfaction, treatment adherence, and clinical outcomes. This article reports on a symposium at the European Charcot Foundation, 2018, led by a panel of leading clinicians and patient experts from MS in the 21st Century, who debated the benefits, drawbacks, and challenges of communicating about disease progression, for both HCPs and PwMS, and potential ways to optimise these discussions. PwMS' preferences and priorities regarding conversations about disease progression vary widely. While the majority want to have these conversations, some will be reluctant and/or emotionally unready. Communication therefore needs to be personalised, and HCPs should always be prepared to have such conversations in an appropriate and sensitive manner. Clinical information can be opaque for PwMS, so HCPs also need to use language that is clear, easily understandable, and patient-friendly. MS in the 21st Century is in the process of developing several resources and programmes to help improve disease progression communication between HCPs and PwMS. FUNDING: Merck KGaA, Darmstadt, Germany. Plain language summary available for this article.

Joint Healthcare Professional and Patient Development of Communication Tools to Improve the Standard of MS Care.

INTRODUCTION: Effective communication between patients and healthcare professionals (HCPs) is important to enhance outcomes in multiple sclerosis (MS). However, in practice, patients often report a disconnect in communication. Communication tools to aid patient-HCP communication have a long history of use in many chronic conditions. For example, symptom diaries have been shown to enhance outcomes in cancer, headache and sleep disorder management. MS in the 21st Century, a Steering Group of HCP specialists and patients with MS (PwMS), has created two communication tools designed for use by both patients and their HCPs. METHODS: The Steering Group first identified prominent issues in patient-HCP communication through group discussions and survey data. Following this, a series of workshops led to the development of two communication tools as potential solutions to these identified issues in communication. RESULTS: The two most prominent issues identified were HCP time constraints during appointments and the misalignment of patient and HCP priorities-the communication tools developed through the workshops were created to address these. The "myMS priorities" tool [see supplementary materials] is designed to maximize the use of consultation time while the "myMS commitments" tool [see supplementary materials] aims to improve patient-HCP shared decision-making. CONCLUSIONS: The MS in the 21st Century Steering Group adopted a broad, iterative and collaborative approach in the development of these tools to help ensure they would be as useful as possible to both HCPs and PwMS. These tools have been developed through shared patient-HCP expertise and are based on existing tools in other therapy areas as well as a review of the existing literature and data from MS in the 21st Century Steering Group surveys. The next steps will focus on the validation of these tools through testing them in real-world environments and clinical trials. FUNDING: Merck KGaA, Darmstadt, Germany.