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•Retinal atrophy in multiple sclerosis (MS) reflects neuroaxonal loss•Retinal thinning was assessed in EXPAND substudy of secondary progressive MS (SPMS)•Siponimod reduced thinning of some retinal layers vs placebo after 1 to 2 years•Retinal atrophy is a potential biomarker of therapeutic efficacy in SPMS

Tolebrutinib is a potent, brain-penetrant and bioactive Bruton's tyrosine kinase (BTK) inhibitor that targets B cells and microglia and has the potential to modulate both peripheral and central pathologic processes in multiple sclerosis (MS) that lead to disability accumulation. Tolebrutinib is being investigated in four phase 3 trials across the spectrum of MS, including non-relapsing secondary progressive MS (nrSPMS) for which there are no approved treatments.

Frexalimab is a second-generation anti-CD40L monoclonal antibody that blocks the costimulatory CD40/CD40L pathway, which is important for activation and function of adaptive and innate immunity. In the phase 2 trial (NCT04879628) in participants with relapsing MS (RMS),frexalimab was well-tolerated and showed an 89% reduction in new gadolinium-enhancing (Gd+)T1 lesions in the high-dose arm vs placebo at week 12. In the ongoing open-label extension, 96%of participants in the high-dose arm were free of Gd+ T1 lesions at week 48.

In a Phase 2 trial (NCT04879628), frexalimab demonstrated effi cacy and safety with high-dosetreatment showing 89% reducti on (versus placebo) in new gadolinium-enhancing T1-lesions atWeek 12 (W12) in parti cipants with relapsing multi ple sclerosis (RMS).

Frexalimab is a second-generation anti-CD40L antibody that blocks the costimulatory CD40/CD40L pathway, which is important in regulating adaptive and innate immunity. In the double-blind period (DBP) of the phase 2 trial in participants with relapsing multiple sclerosis (RMS; NCT04879628), frexalimab treatment was well-tolerated and efficacious at reducing disease activity. Frexalimab 1200 mg intravenous (IV) every 4 weeks (q4w) decreased new gadolinium-enhancing (Gd+) T1 lesions by 89% vs placebo at W12. The treatment effect was sustained over 48 weeks in the open-label extension (OLE).

Frexalimab, a second-generation anti-CD40L monoclonal antibody, demonstrated safety and efficacy in participants with relapsing multiple sclerosis (pwRMS) in the12-week (W) double-blind period of a phase 2 trial (NCT04879628), with an 89% reduction in new gadolinium-enhancing lesions in the high-dose group versusplacebo. This was accompanied by a 24% reduction in plasma neurofilament light (pNfL), a biomarker of neuroaxonal damage. Here, we describe changes in pNfL levelswith frexalimab treatment until W48.

The failure of relapses and white matter lesions to properly explain long-term disability and progression in multiple sclerosis is compounded by its artificial separation into relapsing remitting, secondary progressive, and primary progressive pigeonholes. The well-known epidemiological disconnection between relapses and long-term disability progression has been rediscovered as “progression independent of relapse activity”, i.e. smouldering multiple sclerosis. This smouldering associated worsening proceeds despite early and prolonged use of disease modification therapies, even those that are highly effective at preventing relapses and new/enhancing white matter lesions on MRI. We recognise that smouldering associated worsening and relapse/lesion associated worsening coexist, to varying extents.

Impairment of upper limb function is common in Multiple Sclerosis (MS). Rehabilitation remains a key strategy to manage symptoms and improve quality of life. The Under & Over study assessed the effectiveness of a rehabilitation programme in people with advanced MS.

•Peripheral B cell responses have been targeted to inhibit active/relapsing multiple sclerosis.•Inhibition of advance (progressive) multiple sclerosis may be achieved by targeting B cell responses in the CNS.•Agents exist that could be used to target such B cell responses and could be used to show benefit.

•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.

•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.

•Sexual dysfunction (SD) is a common and distressing symptom for people with multiple sclerosis (MS). Populations included in studies of SD may not fully reflect the diversity of people living with MS.•We evaluated 204 studies including 77,902 participants. Of these, 98 included both male and female participants; 78 included females only, and 27 males only. No studies reported including non-binary patients or gender identities other than male or female.•The overwhelming majority of studies (167/204) did not report sexual orientation. Only 10 studies reported the inclusion of participants who were homosexual and/or bisexual in addition to heterosexual participants.•Whilst studies originated from a range of countries, there were no studies from Central Asia, Eastern Asia, South-Eastern Asia and all subregions of Africa. The geographic spread of papers may have impacted on our findings, as culture, stigma and legal concerns may have limited representation and disclosure.

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.

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.

•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.

•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.

•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.

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.

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.

Resilience; Progressive multiple sclerosis; Genomics

•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.

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.

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.

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.

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.

•Patients stable on natalizumab Q4W can switch to Q6W without meaningful efficacy loss.•Ambulation and dexterity outcomes were similar for Q4W and Q6W.•Patients demonstrated improvements in cognitive processing with both Q4W and Q6W.•Similar proportions of patients reported improvements in disability with Q4W or Q6W.•There were no significant differences between Q4W and Q6W for all PROs in NOVA.

Cladribine tablets (CladT) are an immune reconstitution therapy for the treatment of relapsing multiple sclerosis (RMS), involving two short courses of treatment in Year 1 and Year 2. Beyond the therapeutic phase of treatment, physicians have questions relating to the long-term management of these patients. Since approval of CladT in the EU over 5 years ago, real-world evidence (RWE) is increasing, offering insights for clinical practice.