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Highlights • Long-term lymphocyte counts were evaluated (CLARITY, CLARITY Extension and PREMIERE). • Absolute lymphocyte counts were evaluated to 312 weeks, B and T cells to 240 weeks. • The results suggest that cladribine tablets may be an immune reconstitution therapy. Abstract Background Immune reconstitution therapies (IRT) for patients with multiple sclerosis are used for short, intermittent treatment periods to induce immune resetting and allow subsequent treatment-free periods. Cladribine tablets are postulated to be an IRT that causes selective and transient reductions in CD19+ B cells and T cells, followed by reconstitution of adaptive immune function. Objective To characterize long-term lymphocyte count changes in pooled data from the 2-year CLARITY and subsequent 2-year CLARITY Extension studies, and the PREMIERE registry (Long-term CLARITY cohort). Methods Data from patients randomized to placebo (n = 435) or cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg; n = 685) in CLARITY or CLARITY Extension, including time spent in the PREMIERE registry were pooled to provide long-term follow-up data. The study investigated absolute lymphocyte counts (ALC) up to 312 weeks and B and T cell subsets up to 240 weeks after the first dose, in patients receiving placebo or cladribine tablets 3.5 mg/kg administered as two short (4 or 5 days) weekly treatments at the start of months 1 and 2 in each treatment year, followed by no further active treatment. Results Treatment with cladribine tablets 3.5 mg/kg resulted in selective reductions in B and T lymphocytes. Lymphocyte recovery began soon after treatment in each of years 1 and 2. Median ALC recovered to the normal range and CD19+ B cells recovered to threshold values by week 84, approximately 30 weeks after the last dose of cladribine tablets in year 2. Median CD4+ T cell counts recovered to threshold values by week 96 (approximately 43 weeks after the last dose of cladribine tablets in year 2). Median CD8+ cell counts never dropped below the threshold value. Conclusion These results show the dynamics of lymphocyte count changes following treatment with cladribine tablets 3.5 mg/kg. The immune cell repopulation results provide further evidence that cladribine tablets may represent a form of IRT. [ABSTRACT FROM AUTHOR]

Highlights • Integrated safety of cladribine tablets from Phase 3 trials & PREMIERE is reported. • A Monotherapy Oral cohort and an All Exposed cohort were evaluated. • Most TEAEs (mainly lymphopenia) were expected with cladribine due to mode of action. • No increased risk for infections with cladribine tablets except for herpes zoster. • There was no increase in malignancy rates for cladribine in patients with MS. Abstract Background Treating patients with relapsing multiple sclerosis (MS) with cladribine tablets (two times 4 or 5 days of treatment each year for 2 years) results in long-lasting efficacy, with continued stability in many patients for 4 or more years. Safety and tolerability outcomes from individual clinical studies with cladribine tablets have been reported previously. Objective Report safety data from an integrated analysis of clinical trials and follow-up in patients with MS to further characterize the safety profile of cladribine tablets. Methods Data for patients treated with cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg) as monotherapy (n = 923) or placebo (n = 641) in Phase III clinical trials (CLARITY, CLARITY Extension and ORACLE-MS) and followed up in the PREMIERE registry were aggregated (Monotherapy Oral cohort). To better characterize rare events, additional data from earlier studies which involved the use of parenteral cladribine in patients with MS, and the ONWARD study, in which patients were given cladribine tablets in addition to interferon (IFN)-β or placebo plus IFN-β were included in an All Exposed cohort (cladribine, n = 1926; placebo, n = 802). Adjusted adverse events incidences per 100 patient-years (Adj-AE per 100 PY) were calculated for the integrated analyses. Results The incidence rate of treatment-emergent adverse events (TEAEs) in the Monotherapy Oral cohort was 103.29 vs. 94.26 Adj-AEs per 100 PY for placebo. TEAEs that occurred more frequently with cladribine tablets were mainly driven by the TEAEs of lymphopenia (Adj-AE per 100 PY 7.94 vs. 1.06 for placebo) and lymphocyte count decreased (Adj-AE per 100 PY 0.78 vs. 0.10 for placebo) as anticipated due to the mode of action of cladribine. An increase in TEAE incidence rate was also observed in the cladribine tablets 3.5 mg/kg group vs. placebo for herpes zoster (Adj-AE per 100 PY 0.83 vs. 0.20, respectively). There were no cases of systemic, serious disseminated herpes zoster attributed to treatment with cladribine tablets. In general there was no increase in the risk of infections including opportunistic infections with cladribine tablets versus placebo, except for herpes zoster. Periods of severe lymphopenia (< 0.5 × 109 cells/L) were associated with an increased frequency of infections, but the nature of these was not different to that observed in the overall patient group treated with cladribine tablets 3.5 mg/kg. Within the constraints of a limited sample size, malignancy rates in the overall clinical program for cladribine in MS did not show evidence of an increase compared to placebo-treated patients and there was no increase in the incidence of malignancies over time in cladribine-treated patients. Conclusion The AE profile for cladribine tablets 3.5 mg/kg as a monotherapy has been well-characterized in a pooled population of patients from early to more advanced relapsing MS. There was no increased risk for infections in general except for a higher incidence of herpes zoster. Lymphopenia was amongst the most frequently observed TEAEs that occurred at a higher incidence with cladribine relative to placebo. There was also no increase in malignancy rates for cladribine relative to placebo. [ABSTRACT FROM AUTHOR]

• Treatment-induced, early and late neutropenia can develop in MS. • B-cell depletion shows a low but detectable neutropenia risk. • Neutropenia risk is a balance of neutrophil production verses activity and death. • Neutropoiesis can be inhibited by immune dyscrasia favouring B cell recovery. Neutropenia serves as a risk factor for severe infection and is a consequence of some immune-depleting immunotherapies. This occurs in people with multiple sclerosis following chemotherapy-conditioning in haematopoietic stem cell transplantation and potent B cell targeting agents. Whilst CD52 is expressed by neutrophils and may contribute to early-onset neutropenia following alemtuzumab treatment, deoxycytidine kinase and CD20 antigen required for activity of cladribine tablets, off-label rituximab, ocrelizumab, ofatumumab and ublituximab are not or only weakly expressed by neutrophils. Therefore, alternative explanations are needed for the rare occurrence of early and late-onset neutropenia following such treatments. This probably occurs due to alterations in the balance of granulopoiesis and neutrophil removal. Neutrophils are short-lived, and their removal may be influenced by drug-associated infections, the killing mechanisms of the therapies and amplified by immune dyscrasia due to influences on neutropoiesis following growth factor rerouting for B cell recovery and cytokine deficits following lymphocyte depletion. This highlights the small but evident neutropenia risks following sustained B cell depletion with some treatments [Display omitted] [ABSTRACT FROM AUTHOR]

Cladribine tablets 3.5mg/kg is an established disease-modifying therapy for patients with multiple sclerosis (MS). Objectives: Provide continual presentation of new post-approval safety data concerning cladribine tablets as they become available. Adverse events (AEs) from post-approval sources (including spontaneous individual case safety reports, non-interventional post-marketing studies, and reports from other solicited sources) are presented to July 2023. AE rates are shown as cumulative crude incidences for an estimated population of 78,613 patients treated with cladribine tablets since approval in 2017. Cumulative crude AE incidences were: hypersensitivity, 0.030 (2368 reports); serious infections, 0.01 (1028 reports); herpes zoster, 0.01 (665 reports); liver injury, 0.006 (488 reports); malignancies, 0.004 (285 reports); serious lymphopenia, 0.002 (151 reports); seizures, 0.002 (133 reports); tuberculosis, 0.0003 (26 reports); and opportunistic infections other than progressive multifocal leukoencephalopathy and tuberculosis, 0.0003 (22 reports). Cumulatively, 333 pregnancies have been identified. Among 127 pregnancies with known outcomes, there were 77 live births without congenital anomalies, 21 spontaneous abortions, 23 elective terminations, and two reports of ectopic pregnancy; four pregnancies resulted in live births with congenital anomalies (one major [atrial septal defect] and three minor). Cumulative to July 2023, the safety profile of cladribine tablets is consistent with findings from the clinical development program and previous safety updates. While data are currently scant, there is no evidence for an increased risk of adverse pregnancy outcomes in patients receiving cladribine tablets. [ABSTRACT FROM AUTHOR]

Evobrutinib (EVO), a highly selective, central nervous system-penetrant, covalent Bruton's tyrosine kinase inhibitor, has shown a significant effect on magnetic resonance imaging disease activity, sustained reduction in annualised relapse rate, and stable Expanded Disability Status Scale over >4.5 years (y) in patients (pts) with relapsing multiple sclerosis (PwRMS) in the Phase 2 study. Here, we report the effects of EVO on patient-reported outcomes comprising vitality (VT) and mental health (MH) known to impact PwRMS. In the 48 week (W), PwRMS (n=267) were randomised to placebo (PBO; switched to EVO 25mg once daily [QD] at W24), EVO (25mg QD, 75mg QD, or 75mg twice-daily [BID]; fasted), or open-label dimethyl fumarate (data not reported). Data for pts receiving PBO or EVO 25mg QD were pooled (PBO/EVO low dose). At W48, pts could enter the open-label extension (OLE). Descriptive summary statistics were used to assess changes from baseline (BL) and change categories. A Mixed Model for Repeated Measures was used for inferential analysis up to W48. Pts receiving EVO 75mg BID in the DBP showed significant improvements from BL to W48 versus (vs) PBO/EVO low dose for VT (mean±standard deviation [SD]: 3.2±8.8 vs −1.5±8.2, p=0.0032) and MH (3.4±11.2 vs −0.2±7.8, p=0.0365). Proportions of pts with a clinically meaningful improvement (≥5 points) from BL to W48 in VT and MH were numerically higher for EVO 75mg BID (32.6%, 37.0%) vs EVO 75mg QD (20.0%, 17.8%) and PBO/EVO low dose (17.4%, 25.6%). The inverse was true for worsening from BL to W48. EVO's treatment benefit on short form -36 (SF-36) scores was also seen in the OLE over 3.5y. After converting the SF-36 VT score to PROMIS Fatigue T-score, the change from BL to W48 showed significant improvement in pts treated with EVO 75mg BID vs PBO/EVO low dose (mean±SD: −2.7±7.0 vs 1.2±6.5, p=0.0021). EVO treatment resulted in significant and clinically meaningful improvements in both vitality and mental health with a greater benefit for EVO 75mg BID than lower doses. This benefit was also confirmed with conversion to PROMIS Fatigue T-scores providing early evidence, to be confirmed in Phase 3, that EVO may improve fatigue in PwRMS in addition to reducing disease activity. [ABSTRACT FROM AUTHOR]

• Preoperative contact between the patient's neurologist and the anaesthetist is recommended. • Regularly administered DMTs should not be stopped in the pre-operative period. • General anaesthesia is thought to be safe. • There are no absolute contraindications for regional or neuraxial anaesthesia in pwMS. • Both subarachnoid and epidural blocks are considered safe in pregnant women with MS. There is a lack of published guidelines on the management of patients with multiple sclerosis (MS) undergoing procedures that require anaesthesia and respective advice is largely based on retrospective studies or case reports. The aim of this paper is to provide recommendations for anaesthetists and neurologists for the management of patients with MS requiring anaesthesia. This review covers issues related to the anaesthetic management of patients with MS, with a focus on preoperative assessment, choice of anaesthetic techniques and agents, side-effects of drugs used during anaesthesia and their potential impact on the disease evolution, drug interactions that may occur, and the need to use monitoring devices. A systematic PubMed research was performed to retrieve relevant articles. [ABSTRACT FROM AUTHOR]

Highlights • Disease characteristics outside of licensed applications and commissioning policies mean that many people with multiple sclerosis (pwMS), notably those with progressive MS, have no access to disease modifying treatments (DMTs). • We made generic subcutaneous cladribine available to pwMS with evidence of disease activity including patients who failed or did not tolerate licensed DMTs. • A personalised dosing schedule, and anti-viral prophylaxis, helped avoiding severe lymphopenia and viral infections, and was well tolerated. • Cladribine personalised dosing provides a safe treatment option enabling access to DMT outside NHSE commissioning guidelines for high-cost DMTs. Abstract Background Whilst there is a broad selection of drugs licensed as disease modifying treatments (DMTs) for people with relapsing multiple sclerosis (pwRMS), access to DMTs remains restricted, particularly for people with progressive MS (pwPMS). Cladribine has shown efficacy at all stages of MS. Following withdrawal from the market of oral cladribine in 2011, partly due to issues associated with lymphopenia, and following a thorough risk assessment, we started using subcutaneously injected cladribine (Litak®) to treat both pwRMS and pwPMS. Here, we report on the real life safety and tolerability of this treatment option. Methods Cladribine was offered to (i) pwRMS as a choice despite fulfilling NHS England (NHSE) criteria for licensed DMTs, and (ii) pwRMS and pwPMS not eligible for NHSE approved DMTs. To avoid lymphocyte depletion lower than 0.5 × 109/l (WHO grade 2) cladribine was administered using a personalised dosing scheme (30–40 mg in week 1; and another 0–30 mg in week 5 pending total lymphocyte count at week 4). Anti-viral prophylaxis was given from day 1 for 60 days. Patients approaching week 48 were given a second treatment cycle. Data collection included side effects, relapses, change in disability and MRI indices. Results Seventy-one pwMS (40 female, 31 male; 36 RMS, 35 PMS,) received at least one treatment cycle. Mean age for starting cladribine was 44 years (range 22–72 years), median EDSS was 5 (range 1–8.5). Maximum follow-up was 28 months. 35/71 pwMS were followed up for at least 20 weeks. These patients had a median EDSS of 5.0 (range 1.0–7.5) at baseline and 5.5 (range 1.0–8.0) after a mean follow-up of 11 months (range 5–28). Cladribine was well tolerated with very few treatment-related adverse events observed. Personalised dosing led to grade 1–2 lymphopenia in 50% of cases. A single patient developed transient grade 3 lymphopenia. No cases of varicella or other infections were observed. Four/17 people with relapsing MS, experienced a total of six relapses during a mean follow-up of 13 months (range 5–28 months). In people with PMS (n = 18) median EDSS was 5.5 (2.0–7.5) at baseline and 6.0 (2.5–7.5) after a median of 10 months (range 5–18). In pwPMS MRI showed that 25% had active scans at baseline, and 0% at follow-up. Conclusion Personalised dosing of cladribine avoided severe lymphopenia in all but one patients and was very well tolerated across a large spectrum of disease severity. Our data suggests cladribine may offer benefit people with relapsing and progressive MS alike. The personalised protocol used appears safe, however warrants controlled studies to more definitively assess efficacy and safety, particularly in groups of pwMS who are not eligible for licensed DMT including oral cladribine (Mavenclad®). [ABSTRACT FROM AUTHOR]

Abstract Background Although the aetiology of multiple sclerosis (MS) remains elusive, it is clear that Epstein Barr virus (EBV) and possibly other viruses play a role in the pathogenesis of MS. Laboratory evidence suggests that human endogenous retroviruses (HERVs) could also have a role, but no interventional therapy has determined what will happen if HERVs are suppressed. Recent epidemiological evidence indicates patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting HERVs, or other retroelements, that could be implicated in MS. Objectives To systematically investigate the effects of an HIV integrase strand inhibitor, raltegravir, on the number of gadolinium (Gd)-enhanced MRI lesions in people with active relapsing MS. Methods This is a Phase 2a clinical trial where twenty participants were enrolled in a 3 month baseline phase followed by 3 months of treatment with raltegravir 400 mg twice a day. Patients had monthly Gd-enhanced MRI, saliva collection to test for EBV shedding, blood sampling for safety monitoring, virology (including HERVs), measurement of immunological and inflammatory markers; and physical, neurological and quality-of-life assessments. Results All patients completed the six months trial period.The primary outcome measure of MS disease activity was the number of Gd-enhancing lesions observed, and raltegravir had no significant effect on the rate of development of Gd-enhancing lesions during the treatment phase compared with the baseline phase. Additionally, there was no change in secondary outcomes of either disability or quality-of-life measures that could reasonably be attributed to the intervention. There was a significant positive between HERV-W/MSRV (multiple sclerosis related virus) Gag Flix (Fluorescence index) B cells and the number of Gd-enhanced lesions at any visit (p = 0.029), which was independent of any potential influence of the trial drug administration. Regarding EBV shedding, there was no significant correlation between the amount of EBV shedding and the number of lesions. No change was detected in inflammatory markers (IL-8, IL-1β, IL-6, IL-10, TNF, IL-12p70 and HCRP), which were all within normal limits both before and after the intervention. Serum CD163 expression was also unchanged by raltegravir. Conclusions Raltegravir did not have any impact on MS disease activity. This could be due to the choice of antiretroviral agent used in this study, the need for a combination of agents, as used in treating HIV infection, the short treatment period or dosing regimen, or the lack of a role of HERV expression in MS once the disease is established. Borderline significance for the association between EBV shedding and the total number of lesions, probably driven by new lesion development, may indicate EBV shedding as a marker of inflammatory disease activity. In conclusion, interesting correlations between HERV-W markers, EBV shedding and new MRI lesions, independent from treatment effects, were found. [ABSTRACT FROM AUTHOR]

Highlights • People with advanced (“progressive”) MS (pwPMS) currently have only one licensed disease modifying treatment (DMT) option (ocrelizumab), and this option is highly restricted to a specific MS subpopulation living in high cost economies. • The cerebro-spinal fluid (CSF) neurofilament light chain (NfL) level is a sensitive index of ongoing neuro-axonal damage. • pwPMS who had significantly elevated NfL levels alongside MRI detectable disease activity, were treated using off-label injectable cladribine. • Cladribine was well tolerated without any side effects and led to reduction of disease activity as indicated by a substantial drop in CSF NfL concentration alongside reduction in active MRI lesions, whilst total lymphocyte counts remained within the normal reference range. Abstract Background Evidence suggests people with non-relapsing deteriorating (“progressive”) multiple sclerosis (pwPMS) may benefit from disease-modifying immune therapy (DMT). However, only one such treatment (ocrelizumab) has been licensed and is highly restricted to pwPMS suffering from the primary progressive phenotype. The difficulties assessing treatment outcome in pwPMS is one important reason for the lack of respective DMT. The concentration of neurofilaments in the cerebrospinal fluid (CSF) provides a biomarker of neuro-axonal damage, and both neurofilament light (NfL) and heavy chain (NfH) levels have been used as outcome indices and to guide treatment choices. Methods We report on two pwPMS, who were treated with subcutaneous cladribine undergoing CSF NfL testing, alongside MRI and clinical follow-up, before and after treatment. Results Cladribine treatment was well tolerated without any side effects. CSF NfL after treatment revealed significant reduction (by 73% and 80%, respectively) corroborating the MRI detectable drop in disease activity. Disability mildly progressed in one, and remained stable in the other pwPMS. Conclusions pwPMS with detectable disease activity (MRI, elevated NfL) should be considered for DMT. NfL appears to be a sensitive index of treatment effect in pwPMS, and may be a useful outcome in clinical trials targeting this patient group. Over and above its licensed indication (relapsing MS), cladribine may be an effective treatment option for pwPMS. [ABSTRACT FROM AUTHOR]

Ethical concerns have been raised about the practice of using teriflunomide, an oral licensed disease-modifying therapy, as an active comparator in phase 3 multiple sclerosis (MS) trials. The assumption is based on the perceived low efficacy of teriflunomide as judged by its effect on relapses and focal MRI activity. However, when you look beyond focal inflammation, teriflunomide has a robust impact on disability progression and a similar effect to the anti-CD20 monoclonal antibody therapies on slowing down the accelerated brain volume loss associated with MS. Teriflunomide is also more effective when used second or third line. The other classes of disease-modifying therapies have problems with their use as active comparators in clinical trials. Using a non-inferiority or equivalence trial design has its own unique set of regulatory and ethical challenges and is not necessarily a solution. There are also economic, altruistic and pragmatic reasons for continuing to use teriflunomide as an active comparator in MS clinical trials. An online survey indicates that the majority of the MS community feels it is still ethical to randomise subjects to teriflunomide and that procedures can be put in place to protect trial subjects randomised to teriflunomide. Therefore, we still have equipoise, and teriflunomide comparator trials are ethical. [ABSTRACT FROM AUTHOR]

Resilience; Progressive multiple sclerosis; Genomics [ABSTRACT FROM AUTHOR]

• Disease-modifying therapies (DMTs) have transformed outcomes in multiple sclerosis. • Many DMTs used in multiple sclerosis (MS) are biologic medicines. • In other therapy areas, biologics have been succeeded by biosimilar medicines. • Biosimilar medicines may provide a cost-effective alternative to biologic MS DMTs. • Appropriate education is key for successful adoption of biosimilar medicines. The treatment paradigm for multiple sclerosis (MS), particularly relapsing-remitting MS, is heavily reliant on biologic disease-modifying therapies (DMTs). However, the current cost of treatment acts as a significant barrier to access for patients. Over the next few years exclusivity periods for key biologic medicines used in MS are likely to end, opening the door for biosimilar medicines to enter the market. In this review, we discuss what biosimilar medicines are, and how the existing experience with biosimilar medicines across multiple therapy areas can inform the assimilation of biosimilar medicines into the MS treatment landscape in Europe and the US. There is currently a lack of knowledge and awareness around the distinctions and similarities between small molecules, non-biological complex drugs, and biological medicines, as well as the different categories of follow-on successor medicines. These include biosimilar medicines that offer a matching efficacy and safety profile to the reference biologic. Understanding and recognition of the stringency of the approval pathways required for drug categories such as biosimilars are key in building confidence in treatment outcomes. For example, biosimilar medicines are sometimes perceived only as 'copies' of their reference biologic despite undergoing an extensive approval process requiring that no clinically meaningful differences are observed between the biosimilar medicine and the reference medicine. For MS, introduction of biosimilar medicines in the future will enable more people with MS to receive effective treatment, and also expand access to biologic DMTs in MS. Experiences from the use of biosimilars in multiple therapy areas have shown us that this can result in cost-saving benefits for a healthcare system. Introduction of biosimilar medicines in other therapy areas has also demonstrated the importance of appropriate, accurate education and information for their successful integration into clinical practice. In order to realize optimized treatment outcomes in MS in coming years and to find the appropriate place for biosimilar medicines in the changing MS landscape, it is essential that clinicians and people with MS understand the fundamentals of biosimilars, their potential benefits and consistency of treatment provided by a biosimilar medicine, given the matching efficacy and safety profile to its reference medicine. As evidenced in other therapy areas, biosimilar medicines may reduce key barriers to access by providing a cost-effective alternative to the MS treatment arsenal, while providing the same treatment outcomes as reference biologics. [Display omitted] [ABSTRACT FROM AUTHOR]

Background Patient engagement is vital in multiple sclerosis (MS) in order to optimise outcomes for patients, society and healthcare systems. It is essential to involve all stakeholders in potential solutions, working in a multidisciplinary way to ensure that people with MS (PwMS) are included in shared decision-making and disease management. To start this process, a collaborative, open environment between PwMS and healthcare professionals (HCPs) is required so that similarities and disparities in the perception of key areas in patient care and unmet needs can be identified. With this patient-centred approach in mind, in 2016 the MS in the 21st Century Steering Group formed a unique collaboration to include PwMS in the Steering Group to provide a platform for the patient voice. Methods The MS in the 21st Century initiative set out to foster engagement through a series of open-forum joint workshops. The aims of these workshops were: to identify similarities and disparities in the perception and prioritisation in three key areas (unmet needs, the treatment burden in MS, and factors that impact patient engagement), and to provide practical advice on how the gaps in perception and understanding in these key areas could be bridged. Results Combined practical advice and direction are provided here as eight actions: 1. Improve communication to raise the quality of HCP–patient interaction and optimise the limited time available for consultations. 2. Heighten the awareness of ‘hidden’ disease symptoms and how these can be managed. 3. Improve the dialogue surrounding the benefit versus risk issues of therapies to help patients become fully informed and active participants in their healthcare decisions. 4. Provide accurate, lucid information in an easily accessible format from reliable sources. 5. Encourage HCPs and multidisciplinary teams to acquire and share new knowledge and information among their teams and with PwMS. 6. Foster greater understanding and awareness of challenges faced by PwMS and HCPs in treating MS. 7. Collaborate to develop local education, communication and patient-engagement initiatives. 8. Motivate PwMS to become advocates for self-management in MS care. Conclusion Our study of PwMS and HCPs in the MS in the 21st Century initiative has highlighted eight practical actions. These actions identify how differences and gaps in unmet needs, treatment burden, and patient engagement between PwMS and HCPs can be bridged to improve MS disease management. Of particular interest now are patient-centred educational resources that can be used during time-limited consultations to enhance understanding of disease and improve communication. Actively bridging these gaps in a joint approach enables PwMS to take part in shared decision-making; with improved communication and reliable information, patients can make informed decisions with their HCPs, as part of their own personalised disease management. [ABSTRACT FROM AUTHOR]

Background Daclizumab beta is a humanized monoclonal antibody specific for the human interleukin-2 receptor alpha chain (CD25). In two pivotal studies in relapsing multiple sclerosis (MS), patients treated with daclizumab beta exhibited lower annualized relapse rates (ARR) when compared with placebo or with intramuscular (IM) interferon beta-1a. Objectives To determine if the efficacy of daclizumab beta demonstrated in the phase 2 SELECT study and the phase 3 DECIDE study was consistent in patient subgroups. Methods In the SELECT study, patients received daclizumab beta 150 or 300 mg administered subcutaneously every 4 weeks for 52 weeks, and were compared with patients who received placebo. In the DECIDE study, patients received daclizumab beta 150 mg administered subcutaneously every 4 weeks for 96–144 weeks, and were compared with patients who received IM interferon beta-1a 30 µg. Subgroups were defined by sex, age, the number of relapses in the year before the study, disease duration, baseline disability measured by EDSS, presence of Gd-enhancing lesions, T2 hyperintense lesion volume at baseline, and previous interferon beta-1a use. Results Treatment with daclizumab beta was associated with relative lower ARR, with 95% confidence intervals (CIs) below 1 in 13 of 15 subgroups (SELECT study) compared with placebo and in all 17 subgroups compared with interferon beta-1a (DECIDE study). In 2 subgroups in the SELECT study (patients who were older than 35 years of age or who had a disease duration of 10 or more years), the rate ratio point estimate for the ARR was in favor of daclizumab beta but the 95% CI overlapped with 1. The clinical benefits in ARR achieved with daclizumab beta treatment compared with placebo or interferon beta-1a across subgroups were similarly supported by reductions in lesion activity on magnetic resonance images (MRIs). Conclusions These findings suggest that treatment with daclizumab beta is consistently effective among clinically important patient subgroups and support its potential as a viable therapeutic option across the spectrum of relapsing MS. [ABSTRACT FROM AUTHOR]

Background In multiple sclerosis (MS) upper limb neurological impairments, are an important driver of disability and handicap. The gold standard for assessing upper limb function is the 9-hole peg test (9HPT). One disadvantage of the current plastic version is its price, which prevents its widespread use as a self-monitoring tool by the MS community. Objective To develop and validate an affordable cardboard version of 9HPT for patients to self-monitor upper limb function at home. The aim is not to replace the plastic version, which would stay the gold standard in MS centers. Methods We enrolled 177 volunteers, 68 healthy controls and 109 people with MS (pwMS) at varying stages of their disease. Volunteers performed two trials of the 9HPT with their dominant hand and two with their non-dominant hand using both plastic 9HPT and cardboard 9HPT. The primary comparison parameter was the time needed to perform the task. Results The mean score for the cardboard 9HPT was 24.58 (SEM 1.54 s) seconds compared to 26.03 (SEM 1.44 s) seconds for the plastic 9HPT (p = 0.007). However, the two versions of the tests correlated very strongly, r = 0.96 (p < 0.001). The coefficient of variation, repeat-repeat testing, showed less variability with the cardboard version than in the plastic one with 10% and 14%, respectively. Two-thirds of pwMS preferred using the cardboard version. Conclusion This study demonstrates that the cardboard version is at least equivalent to the plastic version of the test with arguably better design attributes making it the preferred option for self-monitoring. [ABSTRACT FROM AUTHOR]

Background Multiple sclerosis (MS) is often considered to be a CD4, T cell-mediated disease. This is largely based on the capacity of CD4 T cells to induce relapsing experimental autoimmune encephalomyelitis (EAE) in rodents. However, CD4-depletion using a monoclonal antibody was considered unsuccessful and relapsing MS responds well to B cell depletion via CD20 B cell depleting antibodies. The influence of CD20 B cell depletion in relapsing EAE was assessed. Methods Relapsing EAE was induced in Biozzi ABH mice. These were treated with CD20-specific (18B12) antibody and the influence on CD45RA-B220 B cell depletion and clinical course was analysed. Results Relapsing EAE in Biozzi ABH failed to respond to the marked B cell depletion induced with a CD20-specific antibody. In contrast to CD20 and CD8-specific antibodies, CD4 T cell depletion inhibited EAE. Conclusion Spinal cord antigen-induced disease in ABH mice is CD4 T cell-dependent. The lack of influence of CD20 B cell depletion in relapsing EAE, coupled with the relatively marginal and inconsistent results obtained in other mouse studies, suggests that rodents may have limited value in understanding the mechanism occurring following CD20 B cell depletion in humans. [ABSTRACT FROM AUTHOR]