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Background: Cladribine is an effective immunotherapy for people with multiple sclerosis (pwMS). Whilst most pwMS do not require re-treatment following standard dosing (two treatment courses), disease activity re-emerges in others. The characteristics of pwMS developing re-emerging disease activity remain incompletely understood., Objectives: To explore whether clinical and/or paraclinical baseline characteristics, including the degree of lymphocyte reduction, drug dose and lesions on magnetic resonance imaging (MRI) are associated with re-emerging disease activity., Design: Service evaluation in pwMS undergoing subcutaneous cladribine (SClad) treatment., Methods: Demographics, clinical, laboratory and MRI data of pwMS receiving two courses of SClad were extracted from health records. To assess associations of predictor variables with re-emerging disease activity, a series of Cox proportional hazards models was fitted (one for each predictor variable)., Results: Of n  = 264 pwMS 236 received two courses of SClad and were included in the analysis. Median follow-up was 4.5 years (3.9, 5.3) from the first, and 3.5 years (2.9, 4.3) from the last SClad administration. Re-emerging disease activity occurred in 57/236 pwMS (24%); 22/236 received further cladribine doses (SClad or cladribine tablets) at 36.7 months [median; interquartile range (IQR): 31.7, 42.1], and 22/236 other immunotherapies 18.9 months (13.0, 30.2) after their second course of SClad, respectively. Eligibility was based on MRI activity in 29, relapse in 5, both in 13, elevated cerebrospinal fluid neurofilament light chain level in 3, deterioration unrelated to relapse in 4 and other in 3. Only 36/57 of those eligible for additional immunotherapy had received a reduced dose of SClad for their second treatment course. Association was detected between re-emerging disease activity and (i) high baseline MRI activity and (ii) low second dose of SClad., Conclusion: Re-emerging disease activity was associated with baseline MRI activity and low dose second course of SClad., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KA-P, SDT, AMD, AA, LB, TC and DWH have no conflicts of interest to declare. GG has received honoraria and meeting support from AbbVie Biotherapeutics, Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, Sanofi Genzyme, Synthon, Teva and Vertex. He also serves as a chief editor for Multiple Sclerosis and Related Disorders. SG has received honoraria from Biogen Idec, Sanofi Genzyme, Janssen Cilag, Merck, Neurodiem, Novartis, Roche and Teva, and grant support from ECTRIMS, Genzyme, Merck, National MS Society, Takeda, UK MS Society, NIHR and NHSx. MM has received travel support and speaker honoraria from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche and Teva, and consultation for Celgene, Merck Serono, Novartis and Roche. JM has received honoraria and meeting support from Arvelle, Biogen, Novartis, Merck Serono, Roche, Sanofi Genzyme, Jazz Pharmaceuticals, Janssen and Novartis. BPT has received honoraria, travel grants, and has been a member of advisory boards for Biogen, Merck Serono, Novartis, Sanofi Genzyme and Roche. DB has received compensation from InMuneBio, Lundbeck, Merck, Novartis, Rock and Teva. KS has received research support, through Queen Mary University of London, from Biogen, Merck KGaA and Novartis, speaking honoraria from, and/or served in an advisory role for, Biogen, EMD Serono, Merck KGaA, Novartis, Roche, Sanofi-Genzyme and Teva; and remuneration for teaching activities from AcadeMe, Medscape and the Neurology Academy., (© The Author(s), 2023.)

Background: Cognitive problems affect up to 70% of people with multiple sclerosis (MS), which can negatively impact mood, ability to work, and quality of life. Addressing cognitive problems is a top 10 research priority for people with MS. Our ongoing research has systematically developed a cognitive screening and management pathway (NEuRoMS) tailored for people with MS, involving a brief cognitive evaluation and rehabilitation intervention. The present study aims to assess the feasibility of delivering the pathway and will inform the design of a definitive randomised controlled trial (RCT) to investigate the clinical and cost-effectiveness of the intervention and eventually guide its clinical implementation., Methods: The feasibility study is in three parts. Part 1 involves an observational study of those who receive screening and support for cognitive problems, using routinely collected clinical data. Part 2 is a two-arm, parallel group, multicentre, feasibility RCT with a nested fidelity evaluation. This part will evaluate the feasibility of undertaking a definitive trial comparing the NEuRoMS intervention plus usual care to usual care only, amongst people with MS with mild cognitive problems (n = 60). In part 3, semi-structured interviews will be undertaken with participants from part 2 (n = 25), clinicians (n = 9), and intervention providers (n = 3) involved in delivering the NEuRoMS cognitive screening and management pathway. MS participants will be recruited from outpatient clinics at three UK National Health Service hospitals., Discussion: Timely screening and effective management of cognitive problems in MS are urgently needed due to the detrimental consequences of cognitive problems on people with MS, the healthcare system, and wider society. The NEuRoMS intervention is based on previous and extant literature and has been co-constructed with relevant stakeholders. If effective, the NEuRoMS pathway will facilitate timely identification and management of cognitive problems in people with MS., Trial Registration: ISRCTN11203922 . Prospectively registered on 09.02.2021., (© 2022. The Author(s).)

Background: In multiple sclerosis (MS) neurofilament light chain (NfL) is a marker of neuronal damage secondary to inflammation and neurodegeneration. NfL levels drop after commencement of disease-modifying treatment, especially the highly active ones. However, the factors that influence this drop are unknown., Objective: To examine the patient and treatment-related factors that influence CSF NfL before and after starting treatment., Methods: Eligible patients across two centres with two CSF NfL measurements, clinical and MRI data were included as part of an observational cohort study., Results: Data were available in 61 patients, of which 40 were untreated at the first CSF sampling (T1) and treated at the second (T2; mean T1-T2: 19 months). CSF NfL reduction correlated with age (beta = 1.24 95%CI(1.07,1.43); R 2 = 0.17; p = 0.005), Expanded Disability Status Scale (EDSS) (beta = 1.12 95%CI(1.00,1.25); R 2 = 0.21; p = 0.05) and the type of MS (beta = 0.63 95%CI(0.43, 0.92); R 2 = 0.12; p = 0.018; reference=relapsing MS). The treatment effect on a baseline NfL of 702 pg/mL was 451 pg/ml 95%CI(374,509) in a 30-year-old versus 228 pg/ml 95%CI(63,350) in a 60-year-old. There was no association in CSF NfL reduction with BMI, disease duration or sex. In cladribine- and alemtuzumab-treated patients, the CSF NfL T2/T1 ratio did not correlate with lymphocyte depletion rate at 23 weeks., Conclusions: In this observational study, we found that factors reflecting early disease stage, including a younger age, lower disability and relapsing MS were associated with treatment response in CSF NfL. Other factors were not found to be related, including lymphopaenia in highly-active treatments., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To report on safety and effectiveness of subcutaneous cladribine (Litak ® ) in multiple sclerosis (MS) patients., Methods: Litak ® was offered to MS-patients irrespective of disease course. Litak ® 10 mg was administered for 3-4 days during week 1. Based on lymphocyte count at week 4, patients received another 0-3 doses at week 5. A second course was administered 11 months later. Follow-up included adverse events, relapses, expanded disability status scale (EDSS), 9-hole-peg and Timed-25-foot-walking tests, no-evidence-of-disease-activity (NEDA), no-evidence-of-progression-or-active-disease (NEPAD), MRI, cerebrospinal fluid (CSF) neurofilament light chain (NfL), and lymphocyte counts., Results: In all, 208 patients received at least one course of treatment. Age at baseline was 44 (17-72) years and EDSS 0-8.5. Cladribine was generally well tolerated. One myocardial infarction, one breast cancer, and three severe skin reactions occurred without long-term sequelae. Two patients died (one pneumonia, one encephalitis). Lymphopenia grade 3 occurred in 5% and grade 4 in 0.5%. In 94 out of 116 pwMS with baseline and follow-up (BaFU) data after two treatment courses, EDSS remained stable or improved. At 18 months, 64% of patients with relapsing MS and BaFU data ( n  = 39) had NEDA. At 19 months, 62% of patients with progressive MS and BaFU data ( n  = 13) had NEPAD. Of n  = 13 patients whose CSF-NfL at baseline was elevated, 77% were normalised within 12 months., Conclusions: Litak ® was well tolerated. Effectiveness in relapsing MS appeared similar to cladribine tablets and was encouraging in progressive MS. Our data suggest cladribine may be safe and effective in MS-patients irrespective of their disease stage., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.A.P., S.D.T., Z.M., A.M., A.S., X.Z., O.Y., A.A., L.B., C.C., C.D., S.P., L.P.J., B.S. and S.W. have no conflicts of interest to declare. C.A.G. is a founder of NeuroCreare Ltd. J.M. has received honoraria and meeting support from Arvelle, Biogen, Novartis, Merck Serono, Roche and Sanofi Genzyme. C.B. has received travel costs and honoraria from Novartis, Genzyme, Teva and Biogen. K.C. has received honoraria and travel grants from Biogen, Sanofi-Genzyme and Roche. C.S.C. has received support for research, attendance of conferences, and consultancy from Biogen, GW Pharmaceuticals, Novartis, Teva, Merck, Morphosys, Roche, Sanofi Pasteur MSD and Sanofi Genzyme. R.A.F. has received honoraria and consultancy fees from Merck, TEVA, Novartis, Genzyme, GW Pharma, Allergan, Merz, Ipsen, and Biogen. R.A.F.’s current research activity is supported by the NIHR Biomedical Research Centre UCLH. L.F. has received consultancy fees from Biogen, Novartis, Roche and Genzyme. L.F. has received support for educational events from Biogen, Genzyme, Merck, Novartis, Teva, and the Neurology Academy. H.F. has received support from the Health Technology Assessment Programme (NIHR) and the UK MS Society. In the past 3 years, H.F. has been a local principal investigator for trials in MS funded by Novartis, Roche, and Biogen Idec and has taken part in advisory boards and consultancy for Biogen Idec, Merck, Novartis and Roche. B.G. has received personal compensation for consultancy from Merck, Roche, Biogen, Teva UK, and GW Pharma. B.G. has received unrestricted research grants from Biogen Idec, Merck, Bayer Healthcare, Teva UK, Novartis, and Genzyme. B.G. has received support for the attendance of clinical and research conferences from Biogen, Merck, Bayer Healthcare, Teva UK, Novartis, Genzyme, and CelGene. J.H. has received consultancy fees, meeting support, or grants to support clinical services or research from: Biogen Idec, Sanofi Genzyme, Janssen Cilag, Merck, Neurodiem, Novartis, Roche, Celegene, Oxford pharmagenesis. Z.K. has received honoraria and travel costs from Roche, Biogen and Novartis. M.M. has received travel support and speaker honoraria from Biogen Idec, Genzyme, Merck-Sereno, Novartis, Roche and Teva and consultation for Celgene, Merck-Serono, Novartis and Roche. O.P. has received speaking fees and travel expenses from, and/or served on advisory boards for, Biogen, Bayer, Celegene, Janssen, Merck Novartis, Roche, Sanofi and Teva. A.S. has received honoraria, travel grants and been a member of advisory boards for Biogen, Novartis, Teva, Celgene, Sanofi, and Merck. E.S. has received consulting fees and/ or support to attend academic meetings from Merck. E.T. has received honorarium for consulting work from Novartis, Merck, Biogen, and Roche. E.T. has received travel grants to attend or speak at educational meetings from Biogen, Merck, Roche, Takeda, and Novartis. B.P.T. has received honoraria, travel grants, and been a member of advisory boards for Biogen, Merck Serono, Novartis, Sanofi Genzyme, and Roche. M.M. has received honoraria and travel costs from Genzyme, AbbVie, Roche, and Novartis. S.G. has received honoraria from Biogen Idec, Sanofi Genzyme, Janssen Cilag, Merck, Neurodiem, Novartis, Roche, and Teva and grant support from ECTRIMS, Genzyme, Merck, National MS Society, Takeda, and UK MS Society. G.J. has received speaker honoraria from and is a member of advisory boards of AbbVie, Astellas, Celgene, and Novartis. G.G. has received honoraria and meeting support from AbbVie Biotherapeutics, Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, Sanofi Genzyme, Synthon, Teva, and Vertex. He also serves as chief editor for Multiple Sclerosis and Related Disorders. D.B. has received compensation from InMuneBio, Lundbeck, Merck, Novartis, Rock, and Teva. K.S. has received research support from Biogen, Merck KGaA, and Novartis, speaking honoraria from, and/or served in an advisory role for, Amgen, Biogen, EMD Serono, Merck KGaA, Novartis, Roche, Sanofi-Genzyme, and Teva; and remuneration for teaching activities from AcadeMe, Medscape and the Neurology Academy., (© The Author(s), 2021.)

Background: There is an urgent clinical need for reliable remote monitoring methods in Multiple Sclerosis (MS). We evaluated the use of remotely patient-recorded timed 25-foot walk (rT25FW) and nine-hole peg test (r9HPT)., Methods: Seventy-one people with MS completed a previously-validated online EDSS (webEDSS) and r9HPT, and 108 completed the webEDSS and rT25FW., Results: There was a mild-moderate positive correlation between webEDSS and rT25FW, and no significant correlation between webEDSS and r9HPT. Distributions of rT25FW and r9HPT times were positively skewed., Conclusions: Our results provide pilot evidence that remote monitoring of MS is potentially valid but requires refinement before wide-scale implementation. With a median EDSS of 4.5 and EDSS range of 0 - 8.0, at least some patients with ambulatory difficulty are able to complete the assessments., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To evaluate the association between social capital (SC) and the physical and psychological impact of multiple sclerosis (MS)., Materials & Methods: A cross-sectional study was conducted among people with MS (pwMS) at The Royal London Hospital, London, UK. Participants completed a survey including the Multiple Sclerosis Impact Scale-29 (MSIS-29), the Hospital Anxiety and Depression Scale (HADS), the self-reported EDSS and a SC questionnaire (SCQ). The SCQ assessed personal relationships, social support networks, civic engagement, and trust and cooperative norms. Kendall's tau correlation test was performed to measure the correlation between SC and MSIS-29 scores, and multiple linear regressions were conducted to find the best outcome prediction model., Results: 236 pwMS participated in the study. Median age was 43.5 years (IQR 35-52). Of the total, 168 (71.2%) were female and 180 (76.3%) had relapsing-remitting MS. Median MSIS-29 scores were 23.7 (IQR 8.8-57.5) for the physical scale and 38.9 (IQR 16.7-55.6) for the psychological scales. Total SC scores were significantly correlated with the MSIS-29 physical (τb = -0.09, P = .02) and psychological scores (τb = -0.23, P < .001). After adjusting for possible confounders, the "personal relationships" domain had a significant effect on the MSIS-29 physical scores (β = -2.70, SE = 1.34; P = .045). Total SC (β = -1.08, SE = 0.33; P = .001) and the "personal relationships" (β = -2.60, SE = 1.20; P = .031) and "trust and cooperative norms" (β = -1.40, SE = 0.61; P = .024) domains had a significant effect on the MSIS-29 psychological scores., Conclusions: Higher levels of SC were associated with lower physical and psychological impact of MS. Emerging evidence on SC and its effects on MS should be translated into interventions designed to promote the health and well-being of pwMS., (© 2020 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Technological innovation is transforming traditional clinical practice, enabling people with multiple sclerosis (pwMS) to contribute health care outcome data remotely between clinic visits. In both relapsing and progressive forms of multiple sclerosis (MS), patients may experience variable disability accrual and symptoms throughout their disease course. The potential impact on the quality of life (QoL) in pwMS and their families and carers is profound. The introduction of treatment targets, such as NEDA (no evidence of disease activity) and NEPAD (no evidence of progression or active disease), that guide clinical decision-making, highlight the importance of utilizing sensitive instruments to measure and track disease activity and progression. However, the gold standard neurological disability tool-expanded disability severity scale (EDSS)-has universally recognized limitations. With strides made in our understanding of MS pathophysiology and DMT responsiveness, maintaining the status quo of measuring disability progression is no longer the recommended option. Outside the clinical trial setting, a comprehensive monitoring system has not been robustly established for pwMS. A 21st-century approach is required to integrate clinical, paraclinical, and patient-reported outcome (PRO) data from electronic health records, local databases, and patient registries. Patient and public involvement (PPI) is critical in the design and implementation of this workflow. To take full advantage of the potential of digital technology in the monitoring and care and QoL of pwMS will require iterative feedback between pwMS, health care professionals (HCPs), scientists, and digital experts., (Copyright © 2020 Allen-Philbey, Middleton, Tuite-Dalton, Baker, Stennett, Albor and Schmierer.)

Aims: To examine the association between socioeconomic status (SES) and disease-modifying therapy (DMT) prescribing patterns in people with relapsing-remitting multiple sclerosis (pwRRMS)., Methods: A cross-sectional analysis was conducted among pwRRMS treated with a DMT in the neuroinflammation service at The Royal London Hospital (Barts Health NHS Trust). Study data were collected between July and September 2017. SES was determined by patient income and education extracted from the English Index of Multiple Deprivation. Based on their efficacy, DMTs were categorized as moderate efficacy (Glatiramer Acetate and Beta-Interferons), high efficacy (Cladribine, Fingolimod and Dimethyl Fumarate) and very-high efficacy therapies (Natalizumab and Alemtuzumab). Multinomial logistic regressions were performed for univariate and multivariate models to assess differences between SES and DMT prescribing patterns., Results: Treatment consisted of moderate efficacy (n = 76, 12%), high efficacy (n = 325, 51.3%) and very-high efficacy therapies (n = 232, 36.7%). Medians for income and education deciles were 4 (IQR 3-7) and 6 (IQR 4-8), respectively. After multinomial logistic regression analysis, patient income was not associated with increased odds of being treated with high efficacy (OR, 0.92; 95% CI, 0.82-1.04; p = 0.177) or very-high efficacy DMTs (OR, 0.95; 95% CI, 0.85-1.06; p = 0.371). Similarly, patient education was not associated with being treated with high efficacy (OR, 0.91; 95% CI, 0.80-1.03; p = 0.139) or very-high efficacy therapies (OR, 0.92; 95% CI, 0.81-1.04; p = 0.188)., Conclusions: SES was not predictive of DMT prescribing patterns in pwRRMS. Whilst this appears reassuring within this universal health care setting, the same methodology needs to be applied to other MS services for comparison. Data could then be further interrogated to explore potential socioeconomic inequities in DMT prescribing patterns across the UK., Competing Interests: Declaration of Competing Interest SS, KAP, OY, FE and CJ have nothing to declare. SR is supported by an ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) fellowship. JM has received advisory boards fees from Novartis and Merck. GA has received grant support from Biogen. BT has received travel bursaries, grants and advisory boards fees from Biogen, Roche, Sanofi-Aventis, Novartis and Merck. MM has received speaker honoraria from Sanofi-Genzyme and Merck. SG has received speaker honoraria from Genzyme and Novartis. SG has received travel grants from Biogen and ECTRIMS. SG has received grant support from Genzyme and Takeda. KS has received honoraria and meeting support from Biogen, Lipomed, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva. GG has received honoraria and meeting support from AbbVie Biotherapeutics, Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, Sanofi Genzyme, Synthon, Teva and Vertex. GG serves as chief editor for Multiple Sclerosis and Related Disorders., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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 × 10 9 /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 ® )., (Copyright © 2018. Published by Elsevier B.V.)