Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS).

BACKGROUND: Extended interval dosing (EID) of natalizumab is a promising strategy to optimise treatment in multiple sclerosis (MS). Personalised EID by therapeutic drug monitoring can enable further extension of treatment intervals. METHODS: The NEXT-MS trial is an investigator-initiated prospective phase IV non-randomised study. Adults with a diagnosis of relapsing-remitting MS who received ≥6 natalizumab infusions were included in three groups: personalised EID with a target drug trough concentration of 10 µg/mL (EID10), an exploratory group of personalised EID with a target of 5 µg/mL (EID5) and standard interval dosing (SID) of 4 weeks. The primary outcome is radiological disease activity (new/newly enlarged T2 lesions) comparing the EID10 group to a historical cohort of SID (HSID). RESULTS: Results of the first phase of the NEXT-MS trial are reported here (n=376) as the study will continue with an amended protocol. In the EID10 group (n=251), incidence rate of radiological activity was 10.0 per 1000 person-years, which was non-inferior to the HSID cohort (24.7 per 1000 person-years (n=87), incidence rate difference 14.7, 90% CI -4.5 to 34.0). Incidence rate of radiological activity was 10.0 per 1000 person-years in the EID5 group (n=65), and 47.0 per 1000 person-years in the SID group (n=60). Serum neurofilament light levels did not increase over time within the EID groups. There were no cases of progressive multifocal leukoencephalopathy. CONCLUSIONS: MS disease activity is adequately controlled with personalised natalizumab EID. Interval extension to a drug trough concentration of 5 µg/mL is likely a safe target to extend natalizumab treatment intervals >6 weeks. TRIAL REGISTRATION NUMBER: NCT04225312.

A Delphi panel on treatment of high disease activity relapsing remitting multiple sclerosis in the Netherlands.

Aim: To gain insight into current treatment and barriers to optimal treatment for high disease activity relapsing remitting multiple sclerosis (MS) in the Netherlands. Materials & methods: A two-round Delphi panel using an online questionnaire was conducted. Seven MS neurologists from diverse locations in the Netherlands were invited to participate. Result: Out of the seven MS neurologists, five completed both questionnaire rounds. Conclusion: Effectiveness and side effects along with patient's lesion load were the most important factors for choosing a disease modifying therapy (DMTs). Respondents felt restricted to optimally treat their patients due to reimbursement restrictions for certain disease modifying therapies, although agreed that satisfactory treatment options are currently available. The answers show consensus between the participating MS neurologists with high certainty of answers.

Minimal clinically important difference of improvement on the Arm Function in Multiple Sclerosis Questionnaire (AMSQ).

BACKGROUND: The Arm Function in Multiple Sclerosis Questionnaire (AMSQ) has been developed to assess upper extremity function of patients with multiple sclerosis (MS). A minimal clinically important difference (MCID) value has not been determined yet. OBJECTIVE: The objective of this study is to determine an MCID for AMSQ. METHODS: We used the sensitivity- and specificity-based approach with dichotomized global perceived effect as an anchor. RESULTS: The receiver operating characteristic (ROC) curve yielded an optimal threshold value of 14.5 (sensitivity 0.68 and specificity 0.79). The area under the ROC curve value was 0.77. CONCLUSION: We identified an MCID of 15 points for the AMSQ (range 31-186).

Tasks of activities of daily living (ADL) are more valuable than the classical neurological examination to assess upper extremity function and mobility in multiple sclerosis.

BACKGROUND: Accurate clinical assessment in multiple sclerosis (MS) is challenging. The Assess MS system is being developed to automatically quantify motor dysfunction in MS, including upper extremity function (UEF) and mobility. OBJECTIVE: To determine to what extent combinations of standardized movements included in the Assess MS system explain accepted measures of UEF and mobility. METHODS: MS patients were recruited at four European MS centres. Eight movements were selected, including tasks of activities of daily living (ADL) and classical neurological tests. Movements were recorded on video and rated by experienced neurologists (n = 5). Subsequently, multivariate linear regression models were performed to explain the variance of the Nine-Hole Peg Test (9HPT), Arm Function in Multiple Sclerosis Questionnaire (AMSQ) and Timed-25 Foot Walk test (T25WT). RESULTS: In total, 257 patients were included. The movements explained 62.9% to 80.1% of the variance of the 9HPT models, 43.3% and 44.3% of the AMSQ models and 70.8% of the T25WT. In all models, tasks of ADL contributed most to the variance. CONCLUSION: Combinations of movements are valuable to assess UEF and mobility. Incorporating ADL tasks into daily clinical practice and clinical trials may be more valuable than the classical neurological examination of UEF and mobility.

Multidisciplinary data infrastructures in multiple sclerosis: Why they are needed and can be done!

Personalized treatment is highly desirable in multiple sclerosis (MS). We believe that multidisciplinary measurements including clinical, functional and patient-reported outcome measures in combination with extensive patient profiling can enhance personalized treatment and rehabilitation strategies. We elaborate on four reasons behind this statement: (1) MS disease activity and progression are complex and multidimensional concepts in nature and thereby defy a one-size-fits-all description, (2) functioning, progression, treatment, and rehabilitation effects are interdependent and should be investigated together, (3) personalized healthcare is based on the dynamics of system biology and on technology that confirms a patient's fundamental biology and (4) inclusion of patient-reported outcome measures can facilitate patient-relevant healthcare. We discuss currently available multidisciplinary MS data initiatives and introduce joint actions to further increase the overall success. With this topical review, we hope to drive the MS community to invest in expanding towards more multidisciplinary and longitudinal data collection.

Reference videos reduce variability of motor dysfunction assessments in multiple sclerosis.

Motor dysfunction, particularly ataxia, is one of the predominant clinical manifestations in patients with multiple sclerosis (MS). Assessment of motor dysfunction suffers from a high variability. We investigated whether the clinical rating of ataxia can be improved through the use of reference videos, covering the spectrum of severity degrees as defined in the Neurostatus-Expanded Disability Status Scale. Twenty-five neurologists participated. The variability of their assessments was significantly lower when reference videos were used (SD = 0.12; range = 0.40 vs SD = 0.26; range = 0.88 without reference videos; p = 0.013). Reference videos reduced the variability of clinical assessments and may be useful tools to improve the precision and consistency in the clinical assessment of motor functions in MS.