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.

Serum neurofilament light and glial fibrillary acidic protein levels are not associated with wearing-off symptoms in natalizumab-treated multiple sclerosis patients.

BACKGROUND: Biomarkers of neuronal and axonal damage (serum neurofilament light (sNfL) and serum glial fibrillary acidic protein (sGFAP)) may provide insight into the aetiology of natalizumab wearing-off symptoms (WoSs). OBJECTIVES: We investigated the longitudinal association between and predictive value of sNfL and sGFAP and the occurrence of WoS in MS patients treated with natalizumab. METHODS: We performed longitudinal measurements of sNfL and sGFAP in NEXT-MS trial participants who completed a questionnaire about WoS. RESULTS: A total of 364 participants were included. In total, 55.5% presented with WoS and 44.5% without WoS during natalizumab treatment. Longitudinal analyses showed no association between sNfL and sGFAP levels and WoS at any timepoint. Biomarker levels at baseline did not predict first-time WoS occurrence. CONCLUSION: Acute and chronic neuronal and axonal damage are most likely not the underlying cause of WoS.

Differential item functioning of the Arm function in Multiple Sclerosis Questionnaire (AMSQ) by language, a study in six countries.

BACKGROUND: The Arm function in Multiple Sclerosis Questionnaire (AMSQ) has been developed as a self-reported measure of arm and hand functioning for patients with multiple sclerosis (MS). The AMSQ was originally developed in Dutch and to date translated into five languages (i.e. English, German, Spanish, French, and Italian). OBJECTIVE: The aim of this study was to evaluate differential item functioning (DIF) of the AMSQ in these languages. METHODS: We performed DIF analyses, using "language" as the polytomous group variable. To detect DIF, logistic regression and item response theory principles were applied. Multiple logistic regression models were evaluated. We used a pseudo R2 value of 0.02 or more as the DIF threshold. RESULTS: A total of 1733 male and female patients with all subtypes of MS were included. The DIF analysis for the whole dataset showed no uniform or non-uniform DIF on any of the 31 items. All R2 values were below 0.02. CONCLUSION: The AMSQ is validated in six languages. All items have the same meaning to MS patients in Dutch, English, German, Spanish, French, and Italian. This validation study enables use of the AMSQ in international studies, for monitoring treatment response and disease progression.

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).

Personalized extended interval dosing of natalizumab in MS: A prospective multicenter trial.

OBJECTIVE: To determine whether natalizumab efficacy is maintained when switching to personalized extended interval dosing based on individual natalizumab trough concentrations in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: This was a prospective multicenter single-arm trial with 1 year follow-up and a 1-year extension phase. Participants were adult persons with RRMS treated with natalizumab without disease activity in the year prior to enrollment. The natalizumab treatment interval was based on longitudinal natalizumab trough concentrations. Patients received 3 monthly MRI scans, relapse assessments, and disability scoring during follow-up. The primary endpoint was the occurrence of gadolinium-enhancing lesions on MRI. Secondary endpoints were new/enlarging T2 lesions on MRI and relapses and progression on the Expanded Disability Status Scale (EDSS) during follow-up and extension phase. RESULTS: Sixty-one patients were included. Eighty-four percent extended the interval from a 4-week interval to a 5- to 7-week interval. No patient developed gadolinium-enhancing lesions (95% confidence interval [CI] 0%-7.4%) during follow-up. No new/enlarging T2 lesions (95% CI 0%-7.4%) or relapses (95% CI 0%-7.4%) were reported during follow-up and in the extension phase. Median EDSS was comparable at baseline (3.0, interquartile range [IQR] 2.0-5.0) and after follow-up (3.0, IQR 2.0-5.0). CONCLUSION: Personalized extended interval dosing did not induce recurrence of MS disease activity. Natalizumab efficacy was maintained in stable patients with RRMS receiving personalized extended interval dosing based on individual natalizumab concentrations. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that personalized extended interval dosing of natalizumab does not result in recurrence of disease activity in stable patients with RRMS.

Determinants of cerebral atrophy rate at the time of diagnosis of multiple sclerosis.

OBJECTIVE: To identify determinants visible on magnetic resonance imaging of the brain that explain the subsequent rate of cerebral atrophy in patients with recently diagnosed multiple sclerosis. DESIGN: Magnetic resonance imaging of the brain was performed at baseline and after 2 years. T2 hyperintense lesion load, black hole lesion load, presence of contrast-enhancing lesions, and normalized brain volume were derived from the baseline magnetic resonance imaging and considered as possible explanatory variables for the subsequent annualized percentage of brain volume change (PBVC/y) using forward stepwise multiple linear regression analysis. SETTING: MS center Amsterdam, Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands. Patients Eighty-nine patients recently diagnosed as having multiple sclerosis were included at the time of diagnosis from our outpatient clinic. Main Outcome Measure Annualized percentage of brain volume change. RESULTS: The mean (SD) annualized rate of cerebral atrophy was -0.9 (0.8) PBVC/y. Baseline normalized brain volume (standardized coefficient, 0.426; P = .001) and baseline T2 lesion load (standardized coefficient, -0.244; P = .02) were identified as explanatory variables for subsequent PBVC/y and yielded a regression model that explained 31.2% of the variance in PBVC/y. CONCLUSIONS: In patients with recently diagnosed multiple sclerosis, the extent of accumulated brain tissue loss and overall lesion load partly explain the subsequent rate of cerebral atrophy.

Autonomic Dysregulation, Cognitive Impairment, and Symptoms of Psychosis as an Unusual Presentation in an Anti-Aquaporin 4-Positive Patient.

We present the unusual case of a patient with an aquaporin 4 antibody-seropositive neuromyelitis optica spectrum disorder who presented with autonomic dysregulation, cognitive impairment, and symptoms of psychosis. Only a few previous cases have been described with similar psychiatric symptoms. Brain MRI showed an abnormal hyperintense T2 signal of the hypothalamus and, to a lesser extent, a minor hyperintense signal of the right optic nerve. Her symptoms and MR abnormalities improved after high-dose methylprednisolone.

Cognitive impairment and decline in different MS subtypes.

This paper presents results of two studies conducted to investigate cognition in different MS subtypes. First, the results of a study that has previously been published will be discussed. This was a cross-sectional study with 108 relapsing-remitting (RR), 71 secondary progressive (SP), 55 primary progressive (PP) MS patients, and 67 healthy controls [S.C.J. Huijbregts, N.F. Kalkers, L.M.J. de Sonneville, V. de Groot, I.E.W. Reuling, C.H. Polman, Differences in cognitive impairment of relapsing-remitting, secondary and primary progressive MS. Neurology 63 (2004) 335-339]. The second study involved a follow-up assessment after 2 years and included 30 SPMS patients, 25 PPMS patients, and 33 controls. The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) was used for all cognitive assessments. All patient groups demonstrated cognitive deficits compared to healthy controls. RRMS patients were less affected compared to patients with progressive MS subtypes on the Paced Auditory Serial Addition Task (PASAT) and the Symbol Digit Modalities Test (SDMT). These differences were attenuated after control for physical disability level as measured by the Expanded Disability Status Scale. RRMS and SPMS patients were more severely impaired than PPMS patients on the 10/36 Spatial Recall Task and Word List Generation. Results of the follow-up study indicated that both progressive MS subtypes showed a lack of improvement compared to controls on the PASAT and the SDMT, but not on the other tasks of the BRB-N, indicating that performance on tasks requiring multiple abilities concurrently, i.e. visuo-spatial ability and processing speed (SDMT) or working memory and processing speed (PASAT), is most likely to decline across time.

Expression of adhesion molecules on peripheral lymphocytes predicts future lesion development in MS.

The expression of adhesion molecules (alpha4beta1-integrin, LFA-1, ICAM-1) on T cells, measured by flow cytometry, was compared in different subtypes of multiple sclerosis (MS) and related to future lesion development as seen as delta T1 and T2 lesion load per year on magnetic resonance imaging (MRI). LFA-1 and alpha4beta1-integrin showed higher expression on CD4 and CD8 T lymphocytes in the secondary progressive compared to the relapsing-remitting (CD4: p<0.01, p=ns, p<0.05; CD8: p<0.001, p<0.001, p<0.001, respectively) and primary progressive MS phase (CD4: p<0.001, p<0.01, p<0.05; CD8: p<0.01, p<0.01, p<0.001, respectively). The adhesion molecule expression of alpha4- (r=0.31; p<0.05) and beta1-integrin (r=0.38; p<0.01) on CD4+ cells and of LFA-1beta on both CD4+ and CD8+ (r=0.28, p<0.05) and r=0.29; p<0.05, respectively) cells was significantly related to increase in T2 lesion load. Our study provides further evidence for the involvement of integrins in lesion development, shown as T2 lesions on MRI in MS.

Glutamate inhibition in MS: the neuroprotective properties of riluzole.

In addition to demyelination and damage to oligodendrocytes, axonal injury and neuronal cell death are dominating histopathological characteristics of multiple sclerosis (MS). Still little is known about the cause of the damage. Extracellular accumulation of glutamate contributes to excitotoxic injury of neurons and glial cells, suggesting that the maintenance of subtoxic extracellular glutamate levels may be crucial. Riluzole is a neuroprotective agent that inhibits the release of glutamate from nerve terminals and modulates glutamate, i.e., kainate and NMDA receptors. It inhibits excitotoxic injury in several experimental models of neurodegenerative disease. We performed a small run-in versus treatment MR-monitored pilot study in 16 primary progressive MS patients. The results suggest that riluzole reduces the rate of cervical cord atrophy and the development of T1 hypointense lesions on magnetic resonance imaging in primary progressive MS. The rate of brain atrophy was only slightly decreased. The results indicate an effect on mechanisms involving lesion evolution and axonal loss, but no clear effect on new lesion formation. However, the data suffer from several limitations and must be confirmed in future trials.

Longitudinal brain volume measurement in multiple sclerosis: rate of brain atrophy is independent of the disease subtype.

BACKGROUND: In multiple sclerosis (MS), brain atrophy depicted by magnetic resonance imaging reflects overall tissue loss, including axonal loss. OBJECTIVE: To determine the course of atrophy by studying the rate of development of brain atrophy in patients who have different subtypes of MS. METHODS: Eighty-three patients with MS (42 with relapsing-remitting, 21 with secondary progressive, and 20 with primary progressive) were studied longitudinally, with an interval of 2 to 4 years. Magnetic resonance imaging included T1- and T2-weighted images to obtain 2 brain volume measurements: (1) the parenchymal fraction as a marker of global brain atrophy and (2) the ventricular fraction as a marker of central atrophy. The annualized rate of global and central brain atrophy was compared between those with different subtypes of MS and related to clinical characteristics, including sex, age, disease duration, and disability. RESULTS: There was a significant decrease of the parenchymal fraction (-0.7% per year; SEM, 0.11% per year) and a significant increase of ventricular fraction (3.7% per year; SEM, 0.54% per year) in the total group. Significant tissue loss was also seen in all 3 subtypes of MS; the decrease in parenchymal fraction was not different between subtypes, whereas the increase in ventricular fraction tended to be larger in patients with secondary progressive MS compared with patients with primary progressive MS. Marginal associations were found between clinical determinants and the rate of brain atrophy. Annualized increase in the ventricular fraction was correlated with age (r = -0.26) and duration of symptoms (r = -0.22): younger patients (mainly patients with relapsing-remitting MS who have a limited disability) displayed a larger increase in ventricular fraction compared with older patients. CONCLUSIONS: The rate of development of brain atrophy is largely independent of the course of the disease and other clinical characteristics. The relentless loss of tissue occurring in MS is not restricted to later (progressive) phases of the disease, thereby stressing the need for early neuroprotective treatment in MS.

A study validating changes in the multiple sclerosis functional composite.

OBJECTIVE: To prospectively characterize the relation between 1-year changes in neurologist ratings of abnormalities as measured by means of the Expanded Disability Status Scale (EDSS) and changes in observations of functional impairment as measured by means of the Multiple Sclerosis Functional Composite (MSFC) in the clinical assessment of multiple sclerosis (MS). METHODS: One hundred twenty patients with MS were recruited at our outpatient clinic. Impairment and disability at baseline and follow-up were assessed using the EDSS and MSFC. We studied correlations between change (Delta) in the EDSS, MSFC, and MSFC components for the total population and different subgroups and analyzed the contribution of change in MSFC components to change in the EDSS and MSFC. RESULTS: Median EDSS score at baseline was 4.5; at follow-up, 5.0. Mean MSFC score at baseline was -0.00; at follow-up, -0.04. Good cross-sectional correlations were found between the EDSS and MSFC at baseline (-0.72) and follow-up (-0.73). Only weak correlations were found between DeltaEDSS and DeltaMSFC. Although DeltaEDSS showed the strongest correlations with change in leg function and weak or no correlation with change in cognitive function or arm function, DeltaMSFC showed the highest correlation with change in arm function and cognitive function. CONCLUSION: Our longitudinal data indicate that the MSFC reflects change from different dimensions of neurologic functions, which is a favorable characteristic when compared with the EDSS.

Cytokine producing CD8+ T cells are correlated to MRI features of tissue destruction in MS.

Specific T-cell subsets and their ability to produce cytokines have been involved in concepts of multiple sclerosis (MS) pathogenesis. Evidence to link cytokine producing T-cell subsets to magnetic resonance imaging (MRI) features of tissue destruction, however, is limited. Cytokine flow cytometry was performed in 124 patients with different subtypes of MS. In a subgroup of 69 patients, from whom longitudinal MRI was available, the ability of circulating types 1 and 2 helper T cells to produce cytokines was correlated to changes in T1 hypointense and T2 hyperintense lesion load (LL) on brain MRI during 3 years of follow-up. Significant negative correlations were found between baseline CD8(+) T-cell subsets producing IL-2, IL-4 or IL-13 and the change in T1 LL. Subgroup analyses demonstrated that in RRMS, CD8(+) T cells producing IL-2, IL-4 or IL-13, and in PPMS, CD8(+) IL-10(+) T cells correlated negatively with T1 LL. To our knowledge, this study provides the first direct immunophenotypic evidence of cytokine producing CD8(+) T cells being directly related to long-term development of MRI features of demyelination and axonal loss.

Production of IL-1beta and IL-1Ra as risk factors for susceptibility and progression of relapse-onset multiple sclerosis.

Interleukin-1beta (IL-1beta) is present in multiple sclerosis (MS) lesions. Interleukin-1 receptor antagonist (IL-1Ra) moderates the induction of experimental autoimmune encephalomyelitis (EAE). Here, we show that families that are characterized by high IL-1beta over IL-1Ra production ratio are at 2.2-fold (95% CI, 1.0-4.8; p=0.05) increased risk to have a patient relative with relapse-onset MS than families with a low ratio. It is also related to the reduction of volumetric magnetization transfer ratio (MTR) histogram height, a measure of parenchymal integrity (p=0.04). Those families who combine a high IL-1beta over IL-1Ra ratio with a high tumor necrosis factor (TNF) over IL-10 production ratio have a 6.2-fold (95% CI, 1.8-21; p=0.002) increased risk. Innate production of IL-1beta and IL-1Ra is not related to the outcome of primary progressive MS. Taq1 polymorphism in the IL-1beta gene and the variable number of tandem repeats (VNTR) polymorphism of 86-base pairs within the IL-1Ra gene cannot explain these findings.

The interleukin-1 gene family in multiple sclerosis susceptibility and disease course.

Multiple sclerosis (MS) is a chronic disease of presumed autoimmune origin with a considerable polygenic influence. We have previously observed that a specific allele combination in genes of the interleukin-1 (IL-1) family influenced the progression rate in MS. We have considerably expanded our patient population (492 MS patients and 228 controls). In the present study, we investigated the role of the IL-IA--889, IL-1B--511, IL-1B f3953 and IL-1RN VNTR gene polymorphisms in MS. In addition, we performed preliminary analyses on longitudinal magnetic resonance imaging (MRI) data. We found no associations between the polymorphisms and susceptibility to MS or clinical features. In addition, we observed no significant effect of the polymorphisms on brain or lesion volumes, Based on our data and those from the literature, one can conclude that there is currently no evidence to support a role for the IL-1 genes in MS.