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.

Association of age and inflammatory disease activity in the pivotal natalizumab clinical trials in relapsing-remitting multiple sclerosis.

BACKGROUND: Focal inflammatory disease activity in relapsing-remitting multiple sclerosis (RRMS) diminishes with increasing age. Here we use patient-level data from randomised controlled trials (RCTs) of natalizumab treatment in RRMS to investigate the association of age and inflammatory disease activity. METHODS: We used patient-level data from the AFFIRM (natalizumab vs placebo in relapsing-remitting MS, NCT00027300) and SENTINEL (natalizumab plus interferon beta vs interferon beta in relapsing remitting MS, NCT00030966) RCTs. We determined the proportion of participants developing new T2 lesions, contrast-enhancing lesions (CELs) and relapses over 2 years of follow-up as a function of age, and investigated the association of age with time to first relapse using time-to-event analyses. RESULTS: At baseline, there were no differences between age groups in T2 lesion volume and number of relapses in the year before inclusion. In SENTINEL, older participants had a significantly lower number of CELs. During both trials, the number of new CELs and the proportion of participants developing new CELs were significantly lower in older age groups. The number of new T2 lesions and the proportion of participants with any radiological disease activity during follow-up were also lower in older age groups, especially in the control arms. CONCLUSIONS: Older age is associated with a lower prevalence and degree of focal inflammatory disease activity in treated and untreated RRMS. Our findings inform the design of RCTs, and suggest that patient age should be taken into consideration when deciding on immunomodulatory treatment in RRMS.

Relapse recovery in relapsing-remitting multiple sclerosis: An analysis of the CombiRx dataset.

BACKGROUND: Clinical relapses are the defining feature of relapsing forms of multiple sclerosis (MS), but relatively little is known about the time course of relapse recovery. OBJECTIVE: The aim of this study was to investigate the time course of and patient factors associated with the speed and success of relapse recovery in people with relapsing-remitting MS (RRMS). METHODS: Using data from CombiRx, a large RRMS trial (clinicaltrials.gov identifier NCT00211887), we measured the time to recovery from the first on-trial relapse. We used Kaplan-Meier survival analyses and Cox regression models to investigate the association of patient factors with the time to unconfirmed and confirmed relapse recovery. RESULTS: CombiRx included 1008 participants. We investigated 240 relapses. Median time to relapse recovery was 111 days. Most recovery events took place within 1 year of relapse onset: 202 of 240 (84%) individuals recovered during follow-up, 161 of 202 (80%) by 180 days, and 189 of 202 (94%) by 365 days. Relapse severity was the only factor associated with relapse recovery. CONCLUSION: Recovery from relapses takes place up to approximately 1 year after the event. Relapse severity, but no other patient factors, was associated with the speed of relapse recovery. Our findings inform clinical practice and trial design in RRMS.

Threshold definitions for significant change on the timed 25-foot walk and nine-hole peg test in primary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: The timed 25-foot walk (T25FW) and nine-hole peg test (NHPT) exhibit random variability in the short term. A threshold of ≥20% change from baseline has been used to indicate true disability change, but other threshold definitions may be better suited to exclude false and include true change events. The aim of this study was to use patient-level original trial data to investigate the short-term variation in T25FW and NHPT, and to compare its extent with disability change at 12-month follow-up in people with primary progressive multiple sclerosis (PPMS). METHODS: We used original patient-level data from PROMISE, a large PPMS trial. In this trial, three separate T25FW and NHPT measurements were performed 1 week apart during screening. We used these repeated measures to describe the extent of short-term variation. We used binary logistic regression models to investigate the association between screening characteristics and unacceptable short-term variation. RESULTS: The traditional 20% threshold excluded a reasonable number of false change events, while also yielding a large number of change events at follow-up. Increasing index values on the T25FW and NHPT were associated with higher short-term variation. CONCLUSIONS: The traditional ≥20% change threshold for the T25FW and NHPT represents a reasonable compromise between reducing the number of false change events and achieving the largest number of change events in people with PPMS. Our analyses inform the design of clinical trials in PPMS.

Association between age and inflammatory disease activity on magnetic resonance imaging in relapse onset multiple sclerosis during long-term follow-up.

BACKGROUND AND PURPOSE: Inflammatory disease activity in multiple sclerosis (MS) decreases with advancing age. Previous work found a decrease in contrast-enhancing lesions (CELs) with age. Here, we describe the relation of age and magnetic resonance imaging (MRI) measures of inflammatory disease activity during long-term follow-up in a large real-world cohort of people with relapse onset MS. METHODS: We investigated MRI data from the long-term observational Amsterdam MS cohort. We used logistic regression models and negative binomial generalized estimating equations to investigate the associations between age and radiological disease activity after a first clinical event. RESULTS: We included 1063 participants and 10,651 cranial MRIs. Median follow-up time was 6.1 years (interquartile range = 2.4-10.9 years). Older participants had a significantly lower risk of CELs on baseline MRI (40-50 years vs. <40 years: odds ratio [OR] = 0.640, 95% confidence interval [CI] = 0.45-0.90; >50 years vs. <40 years: OR = 0.601, 95% CI = 0.33-1.08) and a lower risk of new T2 lesions or CELs during follow-up (40-50 years vs. <40 years: OR = 0.563, 95% CI = 0.47-0.67; >50 years vs. <40 years: OR = 0.486, 95% CI = 0.35-0.68). CONCLUSIONS: Greater age is associated with a lower risk of inflammatory MRI activity at baseline and during long-term follow-up. In patients aged >50 years, a less aggressive treatment strategy might be appropriate compared to younger patients.

Impact of clinical outcomes and imaging measures on health-related quality of life in secondary progressive MS.

BACKGROUND: Health-related quality of life (HRQOL) outcomes are often included as secondary outcomes in clinical trials in secondary progressive MS (SPMS), but little is known about the longitudinal association of HRQOL and clinical and imaging outcome measures in SPMS. OBJECTIVE: To assess the association of change in clinical and imaging outcomes with HRQOL in people with SPMS. METHODS: We used data from ASCEND, a large randomized controlled trial (n = 889), to investigate the association of significant worsening on the Expanded Disability Status Scale (EDSS), Timed 25 Foot Walk (T25FW), Nine Hole Peg Test (NHPT), Symbol Digit Modalities Test (SDMT), and change in lesional and volumetric imaging outcomes with significant worsening on the 36-Item Short Form Health Survey (SF-36) and the Multiple Sclerosis Impact Scale (MSIS-29) during 2 years of follow-up using logistic regression models. RESULTS: HRQOL measures were most associated with EDSS and T25FW, less so with NHPT and SDMT, and not associated with lesional and volumetric imaging outcomes. DISCUSSION: Worsening of the EDSS and T25FW was associated with two commonly used HRQOL measures. These outcomes therefore appear to be more patient relevant than either the NHPT or SDMT in the context of a 2-year clinical trial.

MRI brain volume loss, lesion burden, and clinical outcome in secondary progressive multiple sclerosis.

BACKGROUND: Magnetic resonance imaging (MRI) of brain volume measures are widely used outcomes in secondary progressive multiple sclerosis (SPMS), but it is unclear whether they are associated with physical and cognitive disability. OBJECTIVE: To investigate the association between MRI outcomes and physical and cognitive disability worsening in people with SPMS. METHODS: We used data from ASCEND, a large randomized controlled trial (n = 889). We investigated the association of change in whole brain and gray matter volume, contrast enhancing lesions, and T2 lesions with significant worsening on the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), Nine-Hole Peg Test (NHPT), and Symbol Digit Modalities Test (SDMT) with logistic regression models. RESULTS: We found no association between MRI measures and EDSS or SDMT worsening. T25FW worsening at 48 and 96 weeks, and NHPT worsening at 96 weeks were associated with cumulative new or newly enlarging T2 lesions at 96 weeks. NHPT worsening at 48 and 96 weeks was associated with normalized brain volume loss at 48 weeks, but not with other MRI outcomes. CONCLUSION: The association of standard MRI outcomes and disability was noticeably weak and inconsistent over 2 years of follow-up. These MRI outcomes may not be useful surrogates of disability measures in SPMS.

The MSIS-29 and SF-36 as outcomes in secondary progressive MS trials.

BACKGROUND: Patient-reported outcome measures (PROMs) are often used in clinical research, but little is known about their performance as longitudinal outcomes. METHODS: We used data from ASCEND, a large SPMS trial (n = 889), to investigate changes on the Short Form Health Survey 36 (SF-36 v2) and the Multiple Sclerosis Impact Scale (MSIS-29) over 2 years of follow-up. RESULTS: PROM scores changed little over the 2 years of follow-up. In contrast to physical disability measures, there was no consistent trend in PROM change: significant worsening occurred about as often as improvement. Using a 6-month confirmation reduced the number of both worsening and improvement events without altering their relative balance. There was no clear difference in worsening events in groups based on population characteristics, nor was there a noticeable effect using different thresholds for clinically significant change. CONCLUSION: We found little consistent change in MSIS-29 and SF-36 over 2 years of follow-up in people with SPMS. Our findings show a disconnect between disability worsening and PROM change in this population. Our findings raise caution about the use of these PROMs as primary outcome measures in SPMS trials and call for a critical reappraisal of the longitudinal use of these measures in SPMS trials.

Early first-line treatment response and subsequent disability worsening in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Treatment success in relapsing-remitting multiple sclerosis (RRMS) is generally determined using relapse frequency and magnetic resonance imaging (MRI) activity in the first 6 or 12 months on treatment. The association of these definitions of short-term treatment success with disability worsening and disease activity in the longer term is unclear. In this study, we investigated risk factors associated with early first-line treatment failure in RRMS, and the association of early treatment failure with subsequent disability worsening or "no evidence of disease activity" (NEDA-3) status. METHODS: We used data from CombiRx (clinicaltrials.gov identifier NCT00211887) to investigate risk factors associated with early treatment failure, and the association of early treatment failure at 6 and 12 months with subsequent disability worsening or NEDA-3 at 36 months. RESULTS: CombiRx included 1008 treatment-naïve participants with RRMS, who were randomly assigned to treatment with glatiramer acetate, interferon beta, or the combination of both. Early treatment failure at 6 or 12 months by several definitions was associated with NEDA-3 failure at 36 months, but not with subsequent disability worsening at 36 months. Expanded Disability Status Scale (EDSS) was the only baseline characteristic associated with the risk of disability worsening at 36 months. Approximately 70% of NEDA-3 failures occurred due to MRI activity, and <10% occurred due to EDSS worsening. CONCLUSIONS: Our investigation shows that current definitions of early treatment failure in RRMS are unrelated to patient-relevant disability worsening at 36 months of follow-up. Further research into useful definitions of treatment success and failure in RRMS is needed.

A comparison of clinical outcomes in PPMS in the INFORMS original trial data set.

BACKGROUND: The expanded disability status scale (EDSS) is the standard clinical outcome measure in primary progressive multiple sclerosis (PPMS), even though the timed 25-foot walk (T25FW), nine-hole peg test (NHPT) or combinations of these measures may be more useful. The paced auditory serial addition test (PASAT) is a widely used cognitive measure in MS, but little is known about change in PASAT scores over time in PPMS. OBJECTIVE: The objective of this study is to compare clinical outcome measures in a large PPMS trial data set. METHODS: We determined significant worsening events on the EDSS, T25FW and NHPT, and PASAT scores over the course of this 3-year trial. We compared unconfirmed, confirmed and sustained disability worsening and contrasted disability worsening with similarly defined improvement. We examined the association of baseline characteristics with the risk of disability worsening at 12, 24 and 36 months with logistic regression models. RESULTS: The EDSS and T25FW showed most worsening events, while only few patients worsened on the NHPT. Adding the NHPT to a combined outcome added only few further worsening events. PASAT scores slightly increased over time, possibly due to a practice effect. CONCLUSION: Both the EDSS and T25FW, but not NHPT or PASAT, appear to be useful outcome measures in PPMS.

Is the Symbol Digit Modalities Test a useful outcome in secondary progressive multiple sclerosis?

BACKGROUND: It is unclear which cognitive outcome measure is the most useful for clinical trials in multiple sclerosis. To investigate the usefulness of the Symbol Digit Modalities Test (SDMT) as a clinical outcome measure in secondary progressive multiple sclerosis (SPMS), we describe the frequency of worsening and improvement events in a large randomized controlled trial (RCT) dataset. METHODS: Using original trial data from the ASCEND trial (n = 889), a recent large RCT in SPMS, we describe worsening and similarly defined improvement with and without 3-month confirmation on the SDMT in the whole trial cohort and unconfirmed worsening and improvement on the Paced Auditory Serial Addition Test (PASAT) in a smaller subset (n = 107). RESULTS: Somewhat unexpectedly, SDMT scores steadily increased throughout the 2 years of follow-up in this trial. There were overall few SDMT worsening events throughout the trial (generally fewer than 10% of participants), but improvement events steadily increased from around 50% of participants with improvement at 12 weeks to more than 70% at 84 weeks and beyond. PASAT scores followed a similar pattern. CONCLUSIONS: In this well-characterized clinical trial cohort, the SDMT does not reflect the steady cognitive decline that patients with SPMS experience. Both SDMT and PASAT scores improve throughout follow-up, possibly due to a practice effect. The SDMT may not be a useful outcome measure of disease progression in 2-year clinical trials in SPMS.

Clinical outcome measures in SPMS trials: An analysis of the IMPACT and ASCEND original trial data sets.

BACKGROUND: Still too little is known about the natural history of clinical outcome measures beyond the Expanded Disability Status Scale (EDSS), such as the timed 25-foot walk (T25FW) and nine-hole peg test (9HPT) in secondary progressive multiple sclerosis (SPMS). OBJECTIVE: To describe progression on the EDSS, T25FW, 9HPT, and their combinations. To investigate the association of the baseline characteristics age, sex, EDSS, T25FW, gadolinium-enhancing lesions, and relapse activity with EDSS and T25FW progression. METHODS: Using original trial data from the placebo arms of the IMPACT and ASCEND randomized controlled trials, we describe disability progression (with and without 3- or 6-month confirmation). We investigated the association of selected baseline characteristics with EDSS and T25FW progression over 2 years using binary logistic regression. RESULTS: T25FW was the single outcome measure with the largest proportion of patients progressing, followed by EDSS and 9HPT. EDSS and T25FW at baseline were associated with EDSS and T25FW progression in both data sets. Age and relapse activity were only mild and inconsistent predictors, while sex and gadolinium enhancement at baseline did not predict disability progression in either data set. CONCLUSION: Our analyses inform the selection of primary outcome measures as well as inclusion criteria for clinical trials in SPMS.

COVID-19 in multiple sclerosis: The Dutch experience.

Here, we provide an extensive overview of all reported COVID-19 cases in multiple sclerosis (MS) patients in the Netherlands between 27 February and 9 June 2020, gathered by the Dutch MS Taskforce of the Netherlands Society of Neurology. A total of 86 MS patients were reported, 43 of whom tested positive for COVID-19. Of 43 patients who tested positive, 22 patients were hospitalized. Three intensive care unit (ICU) admissions and four deaths were reported. Our findings show no apparent difference in disease-modifying treatment (DMT) use and COVID-19 disease course in Dutch MS patients. In addition, a clear link between low lymphocyte count and severe disease was not observed.

Fluoxetine in progressive multiple sclerosis: The FLUOX-PMS trial.

BACKGROUND: Preclinical studies suggest that fluoxetine has neuroprotective properties that might reduce axonal degeneration in multiple sclerosis (MS). OBJECTIVE: To determine whether fluoxetine slows accumulation of disability in progressive MS. METHODS: In a double-blind multicenter phase 2 trial, patients with primary or secondary progressive MS were randomized to fluoxetine 40 mg/day or placebo for a period of 108 weeks. Clinical assessments were performed every 12 weeks by trained study nurses who visited the patients at their home. The primary outcome was the time to a 12-week confirmed 20% increase in the Timed 25 Foot Walk or 9-Hole Peg test. Secondary outcomes included the Hauser ambulation index, cognitive tests, fatigue, and brain magnetic resonance imaging (MRI). RESULTS: In the efficacy analysis, 69 patients received fluoxetine and 68 patients received placebo. Using the log-rank test (p = 0.258) and Cox regression analysis (p = 0.253), we found no significant difference in the primary outcome between the two groups. Due to an unexpected slow rate of progression in the placebo group, there was insufficient statistical power to detect a potential benefit of fluoxetine. We found no differences between the two groups for secondary outcomes. CONCLUSION: The trial failed to demonstrate a neuroprotective effect of fluoxetine in patients with progressive MS.

Cognitive functioning as a predictor of employment status in relapsing-remitting multiple sclerosis: a 2-year longitudinal study.

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 (R2 = 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).

Extremely Painful Multifocal Acquired Predominant Axonal Sensorimotor Neuropathy of the Upper Limb.

The differential diagnosis of upper extremity mononeuritis multiplex includes neuralgic amyotrophy, vasculitic neuropathy, and Lewis-Sumner syndrome. We describe 3 patients initially suspected of neuralgic amyotrophy, who had an extremely painful, protracted, progressive disease course, not fitting one of these established diagnoses. Nerve ultrasonography showed focal caliber changes of the roots, plexus, and limb nerves. Electromyography showed predominant multifocal axonopathy. Ongoing autoimmune neuropathy was suspected. Steroid treatment provided temporary relief, and intravenous immunoglobulin A sustained pain decrease and functional improvement. These patients appear to have extremely painful axonal inflammatory neuropathy, with a good response to immune-modulating treatment.

MRI pattern in asymptomatic natalizumab-associated PML.

OBJECTIVE: To investigate the MRI manifestation pattern of asymptomatic natalizumab-associated progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS). METHODS: 18 patients with MS with natalizumab-associated PML lesions on MRI were included. In 6 patients, the PML lesions were identified on MRI prospectively and in 12 patients PML lesions were identified retrospectively. MRI sequences were analysed for PML lesion distribution, appearance, grey matter/white matter involvement and possible signs of inflammation. Lesion probability maps were created to demonstrate lesion distribution pattern. RESULTS: The frontal lobe was involved in 14 patients (77.8%) and the parietal lobe in 4 patients (22.2%). Most patients presented with focal lesions (13 patients, 72.2%) involving one single lobe (12 patients, 66.7%). The cortical grey matter was affected in 15 patients (83.3%) and 13 patients (72.2%) presented with a combination of cortical grey and white matter involvement. Signs of inflammation were detected in 7 patients (38.8%). Among patients with available diffusion-weighted imaging, 6 patients (40%) did not show high-signal-intensity lesions. A classical imaging pattern including unilateral and unilobar focal lesions in the frontal lobe affecting the cortical grey matter or the cortical grey and adjacent white matter was observed in 8 patients (44.4%). CONCLUSIONS: Asymptomatic natalizumab-associated PML manifestations on MRI show a rather localised disease, frequently located in the frontal lobes, affecting the cortical grey matter and adjacent juxtacortical white matter. Awareness of this lesion pattern facilitates an earlier diagnosis of natalizumab-associated PML in an asymptomatic stage associated with a more favourable prognosis.

Cerebral white matter blood flow and energy metabolism in multiple sclerosis.

BACKGROUND: Cerebral blood flow (CBF) is reduced in normal-appearing white matter (NAWM) of subjects with multiple sclerosis (MS), but the underlying mechanism is unknown. OBJECTIVE: The objective of this article is to assess the relationship between reduced NAWM CBF and both axonal mitochondrial metabolism and astrocytic phosphocreatine (PCr) metabolism. METHODS: Ten healthy controls and 25 MS subjects were studied with 3 Tesla magnetic resonance imaging. CBF was measured using pseudo-continuous arterial spin labeling. N-acetylaspartate/creatine (NAA/Cr) ratios (axonal mitochondrial metabolism) were obtained using (1)H-MR spectroscopy and PCr/ß-ATP ratios using (31)P-MR spectroscopy. In centrum semiovale NAWM, we assessed correlations between CBF and both NAA/Cr and PCr/ß-ATP ratios. RESULTS: Subjects with MS had a widespread reduction in CBF of NAWM (centrum semiovale, periventricular, frontal and occipital), and gray matter (frontoparietal cortex and thalamus). Compared to controls, NAA/Cr in NAWM of the centrum semiovale of MS subjects was decreased, whereas PCr/ß-ATP was increased. We found no correlations between CBF and PCr/ß-ATP. CBF and NAA/Cr correlated in controls (p = 0.02), but not in MS subjects (p = 0.68). CONCLUSIONS: Our results suggest that in MS patients there is no relationship between reduced CBF in NAWM and impaired axonal mitochondrial metabolism or astrocytic PCr metabolism.