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Background and Objectives: Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID., Methods: Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4-7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated., Results: 255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms., Discussion: Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations., Competing Interests: Declaration of competing interest A.A. Toorop: nothing to disclose. M.H.J. Wessels: nothing to disclose. L.M.Y. Gelissen: nothing to disclose. E. Hoitsma: has accepted (speaker and congress) fees from Merck Serono, Biogen Idec, Roche, and Sanofi Genzyme. E.M.P.E. Zeinstra: reports advisory boards/consultancy fees for Merck, Novartis, Genzyme and Roche. L.C. van Rooij: nothing to disclose. C.E.P. van Munster: nothing to disclose. A. Vennegoor: nothing to disclose. J.P. Mostert: nothing to disclose. B.H.A. Wokke: nothing to disclose. N.F. Kalkers: nothing to disclose. E.L.J. Hoogervorst: nothing to disclose. J.J.J. van Eijk: reports honoraria for advisory boards and/or speakers fee from Merck Serono, Biogen Idec, Sanofi Genzyme, Roche and Novartis. C.M. Roosendaal: nothing to disclose. J.J. Kragt: nothing to disclose. M. Eurelings: nothing to disclose. J. Nielsen: nothing to disclose. J. van Genugten: nothing to disclose. L.G.F. Sinnige: nothing to disclose. M.E. Kloosterziel: nothing to disclose. E.P.J. Arnoldus: nothing to disclose. G.W. van Dijk: nothing to disclose. W.H. Bouvy: nothing to disclose. E.M.M. Strijbis: nothing to disclose. B.W. van Oosten: nothing to disclose. B.A. de Jong: nothing to disclose. B.I. Lissenberg-Witte: nothing to disclose. T. Rispens received funding for research from Genmab and consultancy fees from Novartis. B.M.J. Uitdehaag: reports research support and/or consultancy fees from Genzyme, Biogen Idec, Novartis, Teva Pharmaceutical Industries, Merck Serono, Roche, and Immunic Therapeutics. J. Killestein: received research grants for multicentre investigator initiated trials DOT-MS trial, ClinicalTrials.gov Identifier: NCT04260711 (ZonMW) and BLOOMS trial (ZonMW and Treatmeds), ClinicalTrials.gov Identifier: NCT05296161); received consulting fees for F. Hoffmann-La Roche Ltd., Biogen, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F. Hoffmann-La Roche Ltd., Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); adjudication committee of MS clinical trial of Immunic (payments to institution only). Z.L.E. van Kempen: nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Natalizumab is effective in the treatment of multiple sclerosis (MS). In 2021, the European Medicines Agency approved the subcutaneous (SC) variant of natalizumab which can be used instead of intravenous administration. However, the course of drug levels varies between administration routes, and the Food and Drug Administration rejected the request for approval of natalizumab SC for reasons that were not disclosed. Our objective was to evaluate the course of natalizumab trough drug levels in patients who switched from natalizumab intravenous to SC on various treatment intervals., Methods: The NEXT-MS trial (N=382) investigates personalised treatment of natalizumab, in which infusion intervals are prolonged based on individual natalizumab trough drug levels. In 2021, an amendment was approved allowing participants to switch from intravenous to SC administration with frequent measurements of natalizumab drug levels and antidrug antibodies (ADAs). Results were compared with linear mixed model analyses., Results: Until December 2022, 15 participants switched to SC natalizumab. Natalizumab drug levels with SC administration were on average 55% lower compared with intravenous administration (Exp (estimate) 0.45, 95% CI 0.39 to 0.53, p<0.001), leading to very low trough drug levels in three patients on extended treatment intervals. No natalizumab ADAs were detected during intravenous or SC treatment. None of the participants on natalizumab SC showed evidence of MS disease activity., Conclusions: Natalizumab trough drug levels can decrease after switching from natalizumab intravenous to SC administration. We advise to monitor trough drug levels in patients with low natalizumab drug levels during intravenous treatment, patients with higher body mass index or patients on extended treatment intervals who switch to SC administration of natalizumab., Competing Interests: Competing interests: AAT: nothing to disclose. ZLEvK: nothing to disclose. MS: nothing to disclose. JN: nothing to disclose. LGFS: nothing to disclose. GvD: nothing to disclose. CMR: nothing to disclose. EPJA: nothing to disclose. EH: has accepted (speaker and congress) fees from Merck Serono, Biogen Idec, Roche, Novartis, Teva and Sanofi Genzyme. BIL-W: nothing to disclose. BADJ: nothing to disclose. BvO: nothing to disclose. EMS: nothing to disclose. BMJU: received research support and/or consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva and Immunic Therapeutics. TR: received funding for research from Genmab; received consulting fees from Novartis. JK: received research grants for multicentre investigator initiated trials DOT-MS trial, ClinicalTrials.gov Identifier: NCT04260711 (ZonMW) and BLOOMS trial (ZonMW and Treatmeds), ClinicalTrials.gov Identifier: NCT05296161); received consulting fees for F. Hoffmann-La Roche, Biogen, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F. Hoffmann-La Roche, Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); adjudication committee of MS clinical trial of Immunic (payments to institution only)., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: This study aimed to identify mental health, physical health, demographic and disease characteristics relating to work productivity in people with multiple sclerosis (MS)., Methods: In this cross-sectional study, 236 employed people with MS (median age = 42 years, 78.8% female) underwent neurological and neuropsychological assessments. Additionally, they completed questionnaires inquiring about work productivity (presenteeism: reduced productivity while working, and absenteeism: loss of productivity due to absence from work), mental and physical health, demographic and disease characteristics. Multiple linear and logistic regression analyses were performed with presenteeism and absenteeism as dependent variables, respectively., Results: A model with mental and physical health factors significantly predicted presenteeism F (11,202) = 11.33, p  < 0.001, R 2  = 0.38; a higher cognitive ( p  < 0.001) and physical impact ( p  = 0.042) of fatigue were associated with more presenteeism. A model with only mental health factors significantly predicted absenteeism; χ 2 (11)=37.72, p  < 0.001, with R 2  = 0.27 (Nagelkerke) and R 2  = 0.16 (Cox and Snell). Specifically, we observed that more symptoms of depression ( p  = 0.041) and a higher cognitive impact of fatigue ( p  = 0.011) were significantly associated with more absenteeism., Conclusions: In people with MS, both cognitive and physical impact of fatigue are positively related to presenteeism, while symptoms of depression and cognitive impact of fatigue are positively related to absenteeism.Implications for rehabilitationMultiple sclerosis (MS) affects people of working age, significantly interfering with work productivity.Higher cognitive and physical impact of fatigue were associated with more presenteeism in workers with MS.A higher cognitive impact of fatigue and more depressive symptoms were associated with absenteeism in workers with MS.Occupational and healthcare professionals should be aware of the impact of both physical and mental health on work productivity in workers with MS.

Background: Multiple sclerosis (MS) poses a major threat to sustainable employability. Identifying conditions and factors that promote work participation is of great importance. Our objective was to explore the contribution of personality traits in explaining occupational functioning in MS., Methods: 241 participants with relapsing-remitting MS (78% female, median age: 42.0 years, median EDSS: 2.0) and 60 healthy controls (70% female, median age: 45.0 years) underwent neuropsychological and neurological examinations and completed questionnaires. Multivariate logistic and linear regression analyses were conducted to examine relations between personality traits and self-reported occupational functioning, while accounting for known correlates., Results: Personality traits were not associated with self-reported occupational functioning when correcting for known correlates. A higher impact of fatigue (B = -0.05, p = .005 and B = -0.04, p = .009) and depression (B = -0.22, p = .008 and B = -0.21, p = .01) were associated with no paid job (R 2  = 0.13) and considering to reduce work hours (R 2  = 0.12). A higher impact of fatigue (B = -0.05, p = .008, β = 0.46, p = .001 and β = -0.36, p = .001) was associated with absenteeism from work (R 2  = 0.15), more presenteeism (R 2  = 0.35) and lower work ability (R 2  = 0.25). A higher impact of fatigue (β = 0.46, p = .001) and anxiety (β = 0.25, p = .001) were associated with more work difficulties (R 2  = 0.54)., Conclusion: Personality traits did not explain additional variance in self-reported occupational functioning in persons with relapsing-remitting MS with mild disability. The impact of fatigue was the main and most consistent correlate of occupational functioning, often combined with depression or anxiety. Total explained variance of the models was limited, emphasizing the need to additionally examine other (contextual) factors when considering occupational challenges in MS., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cognitive functioning has been linked to employment outcomes in multiple sclerosis (MS) in cross-sectional studies. Longitudinal studies are however lacking and previous studies did not extensively examine executive functioning., Objectives: We examined whether baseline cognitive functioning predicts a change in employment status after 2 years, while taking into account mood, fatigue and disability level., Methods: A total of 124 patients with relapsing-remitting MS (pwMS) and 60 healthy controls were included. They underwent neurological and neuropsychological examinations and completed online questionnaires. PwMS were divided into a stable and deteriorated employment status group (SES and DES), based on employment status 2 years after baseline. We first examined baseline differences between the SES and DES groups in cognitive functioning, mood, fatigue and disability level. A logistic regression analysis was performed, with change in employment status (SES/DES) as dependent variable., Results: The DES group included 22% pwMS. Group differences were found in complex attention, executive functioning, self-reported cognitive functioning, fatigue and physical disability. More physical disability (OR = 1.90, p = 0.01) and lower executive functioning (OR = 0.30, p = 0.03) were retained as independent predictors of DES (R 2  = 0.22, p ≤ 0.001)., Conclusions: Baseline physical disability and executive functioning, but none of the other variables, moderately predicted a deterioration in employment status 2 years later., Trial Registration: This observational study is registered under NL43098.008.12: 'Voorspellers van arbeidsparticipatie bij mensen met relapsing-remitting Multiple Sclerose'. This study is registered at the Dutch CCMO register (https://www.toetsingonline.nl).

Background: The aim of this study was to examine whether work capabilities differ between workers with Multiple Sclerosis (MS) and workers from the general population. The second aim was to investigate whether the capability set was related to work and health outcomes., Methods: A total of 163 workers with MS from the MS@Work study and 163 workers from the general population were matched for gender, age, educational level and working hours. All participants completed online questionnaires on demographics, health and work functioning. The Capability Set for Work Questionnaire was used to explore whether a set of seven work values is considered valuable (A), is enabled in the work context (B), and can be achieved by the individual (C). When all three criteria are met a work value can be considered part of the individual's 'capability set'., Results: Group differences and relationships with work and health outcomes were examined. Despite lower physical work functioning (U = 4250, p = 0.001), lower work ability (U = 10591, p = 0.006) and worse self-reported health (U = 9091, p ≤ 0.001) workers with MS had a larger capability set (U = 9649, p ≤ 0.001) than the general population. In workers with MS, a larger capability set was associated with better flexible work functioning (r = 0.30), work ability (r = 0.25), self-rated health (r = 0.25); and with less absenteeism (r = - 0.26), presenteeism (r = - 0.31), cognitive/neuropsychiatric impairment (r = - 0.35), depression (r = - 0.43), anxiety (r = - 0.31) and fatigue (r = - 0.34)., Conclusions: Workers with MS have a larger capability set than workers from the general population. In workers with MS a larger capability set was associated with better work and health outcomes., Trial Registration: This observational study is registered under NL43098.008.12: 'Voorspellers van arbeidsparticipatie bij mensen met relapsing-remitting Multiple Sclerose'. The study is registered at the Dutch CCMO register ( https://www.toetsingonline.nl ). This study is approved by the METC Brabant, 12 February 2014. First participants are enrolled 1 st of March 2014.

- Even at a young age, multiple sclerosis often profoundly impacts a patient's daily activities.- Treatment is complicated because disease course is different for each patient.- Early treatment has the best results, in the short term as well as the long term, but the most effective treatments can have severe and sometimes irreversible side effects and are very costly.- It is therefore important to determine the prognosis at an early stage, in order to limit increasing future invalidity with appropriate treatment.- For this literature review, we have examined short- and long-term disease course as well as possible prognostic factors.