•A long disease duration at natalizumab initiation predicts earlier EDSS progression.•A higher pre-baseline relapse rate predicts a longer NEPAD status.•Considering early effects of natalizumab, ...43.7% of patients showed progression.•Long-term EDSS improvement was seen in 17.8% of the patients using natalizumab.
Natalizumab is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). Data on clinical and imaging measures predictive of disease activity and progression during treatment is limited.
To determine clinical and imaging predictors of long-term inflammatory disease activity and disability progression in RRMS patients on natalizumab.
Patients (n = 135) were selected from our prospective observational natalizumab cohort and monitored using brain MRI and extensive clinical testing. Progression and improvement on the Expanded Disability Status Scale (EDSS), no evidence of disease activity (NEDA) and no evidence of progression or active disease (NEPAD) status were determined using measurements after the initial phase of inflammation and the early anti-inflammatory impact of natalizumab.
EDSS progression was seen in 43.7% of patients and EDSS improvement in 17.8%. Median follow-up was 4.9 years (IQR 3.6–6.0). Patients with a longer disease duration at natalizumab initiation have a higher hazard for earlier EDSS progression (HR 1.05, CI 1.00–1.09, p = 0.037) and a higher pre-baseline relapse rate predicted a longer NEPAD status (HR 1.70, CI 1.06–2.72, p = 0.028).
The results suggest that starting natalizumab early, during active inflammatory disease results in a more favourable outcome. When taking into account early inflammation and the impact of natalizumab on disease activity during the initial treatment phase, a higher than expected proportion of patients showed disability progression.
Aims
Cell matrix modulating protein SPARCL‐1 is highly expressed by astrocytes during CNS development and following acute CNS damage. Applying NanoLC‐MS/MS to CSF of RRMS and SPMS patients, we ...identified SPARCL‐1 as differentially expressed between these two stages of MS, suggesting a potential as CSF biomarker to differentiate RRMS from SPMS and a role in MS pathogenesis.
Methods
This study examines the potential of SPARCL‐1 as CSF biomarker discriminating RRMS from SPMS in three independent cohorts (n = 249), analyses its expression pattern in MS lesions (n = 26), and studies its regulation in cultured human brain microvasculature endothelial cells (BEC) after exposure to MS‐relevant inflammatory mediators.
Results
SPARCL‐1 expression in CSF was significantly higher in SPMS compared to RRMS in a Dutch cohort of 76 patients. This finding was not replicated in 2 additional cohorts of MS patients from Sweden (n = 81) and Switzerland (n = 92). In chronic MS lesions, but not active lesions or NAWM, a vessel expression pattern of SPARCL‐1 was observed in addition to the expression by astrocytes. EC were found to express SPARCL‐1 in chronic MS lesions, and SPARCL‐1 expression was regulated by MS‐relevant inflammatory mediators in cultured human BEC.
Conclusions
Conflicting results of SPARCL‐1′s differential expression in CSF of three independent cohorts of RRMS and SPMS patients precludes its use as biomarker for disease progression. The expression of SPARCL‐1 by BEC in chronic MS lesions together with its regulation by inflammatory mediators in vitro suggest a role for SPARCL‐1 in MS neuropathology, possibly at the brain vascular level.
To determine characteristics of multiple sclerosis patients that discontinued natalizumab treatment in a real-world cohort.
Data was collected from an ongoing observational cohort study of all ...natalizumab treated patients at the Amsterdam UMC.
Of 253 patients who ever received natalizumab treatment, 147 have discontinued treatment. The most frequent reason for treatment discontinuation was JC-virus (JCV) positivity.
JCV positivity seems the most frequent reason for natalizumab discontinuation. The heterogeneity in treatment switches reflects the advances made in treatment options, and underlines the need for adequate patient counselling.
Background. Natalizumab treatment is frequently discontinued and replaced by alternative medication in multiple sclerosis (MS) patients having a high risk of progressive multifocal ...leukoencephalopathy (PML). Case Presentation. We report a PML case that was missed on magnetic resonance imaging (MRI) at the time Natalizumab treatment was discontinued. The patient subsequently developed a PML-immune reconstitution inflammatory syndrome after the initiation of Fingolimod treatment, suggesting that immune reconstitution may occur even during Fingolimod induced lymphopenia. Conclusion. This report highlights the need for strict drug surveillance using MRI of Natalizumab-associated MS patients at the time of drug discontinuation and beyond. This is important with respect to pharmacovigilance purposes not only for Natalizumab, but also for alternative drugs used after Natalizumab discontinuation.
Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab treatment. Restoring immune function by plasmapheresis/immunoadsorption (PLEX/IA) is important for the outcome ...of PML. We report on four multiple sclerosis (MS) patients whom developed PML during natalizumab treatment, in whom we measured serum natalizumab concentrations before and during PLEX. Depending on the serum natalizumab concentration at the time of PML diagnosis, the number of PLEX treatments necessary to reach subtherapeutic serum natalizumab concentrations is variable. Measuring serum natalizumab concentrations before and during PLEX is helpful to determine the optimum number of PLEX treatments in individual MS patients with PML.
Ocrelizumab is often used as an alternative therapy in natalizumab-treated MS patients at risk for progressive multifocal leukoencephalopathy (PML). Our objective was to assess efficacy and safety of ...JC-virus positive patients switching (either directly or indirectly) from natalizumab to ocrelizumab. Forty-two patients were included from an observational cohort (median follow-up 21 months). No evidence of disease activity was found in 83% of direct switchers and 50% of indirect switchers. Two direct switchers were diagnosed with carry-over PML. Our data support a direct switch for adequate disease suppression, although carry-over PML illustrates the dilemma when choosing between a direct or indirect switch.
Osteopontin (OPN) has been identified as the most prominent cytokine-encoding gene expressed within multiple sclerosis (MS) lesions. Recently, we demonstrated that OPN plasma levels were elevated in ...active relapsing–remitting (RR) MS patients. In this longitudinal study, a trend was observed for OPN serum levels in relation to clinical exacerbations. Moreover, OPN protein levels were significantly elevated 1 month prior to increase of gadolinium (Gd)-enhancing lesion number, whereas no relation was observed between OPN levels and increase in Gd-enhancing lesion volume. Although no robust relation between OPN and disease activity was observed, these data suggest that OPN levels are elevated prior to increased disease activity in RR MS patients.
•Responder rates to fampridine differed between clinical subgroups of MS.•Efficacy was best assessed with walking speed if ambulation was severely impaired.•In cases of mild ambulatory impairment, ...PRO of ambulation was more sensitive.•PROs influenced treatment decision.•Using PROs in conjunction to performance measures helps in treatment decision making.
Fampridine is an effective treatment to improve ambulation for some multiple sclerosis (MS) patients. Remarkable discrepancies exist between responder rates in clinical trials and the proportion of patients continuing treatment in clinical practice. This may be related to clinical phenotypes of MS patients, and the influence of patient reported outcome (PRO) on treatment decision making.
To analyse responder rates to fampridine on ambulation and upper extremity function (UEF) and the influence on treatment decision making in different clinical subgroups in a real-world setting.
MS patients with ambulatory impairment treated with fampridine were included. Patients were subdivided based on disease duration, clinical phenotype, Expanded Disability Status Scale (EDSS), baseline walking speed, and presence of UEF impairment. Ambulatory response was assessed with the Timed 25-Foot Walk (T25FW, responder defined as ≥20% improvement) and with the MS Walking Scale (MSWS, responder defined as ≥8 points improvement) as a PRO. For patients also reporting impaired UEF, the Arm Function in MS Questionnaire (AMSQ, responder defined as ≥15 improvement) was the PRO of choice. Decision on treatment continuation was based on improvement of T25FW, MSWS and the clinicians’ overall impression for improvement.
In total 344 patients were included of which 75.3% continued treatment. More patients with a relapsing clinical phenotype continued treatment vs patients with a progressive phenotype (83.6 vs 68.6%, p < 0.01).
A positive linear trend was found between severity of walking disability, as determined by baseline walking speed, and T25FW response (p < 0.01), while there was an inverse linear association between walking disability and MSWS response (p = 0.03). However, the proportion of patients continuing treatment was similar between subgroups of baseline walking speed. Impaired UEF was reported by 183 (66.5%) patients, of which 64 (39.3%) were AMSQ responders. Patients responding on AMSQ compared to non-responders, were also more frequently MSWS responders (82.8 vs 65.3%, p = 0.02), while response on T25FW was similar, and continued treatment more often (85.9 vs 70.7%, p = 0.04). This suggests an influence of PRO on treatment decision making.
Responder rates and treatment continuation of fampridine differed between clinical subgroups of MS. PROs influenced treatment decision making of fampridine in clinical practice, particularly in patients with mild ambulatory impairment or those reporting UEF impairment. To some extent, these findings explain discrepancies found between clinical trials and clinical practice, and support the importance of subgroup analyses and incorporation of PROs in clinical trials. For clinical practice, using PROs to assess patients experience in conjunction with performance measures helps in treatment decision making.
The authors conducted a randomized, double-blind, placebo-controlled, twofold crossover study in 16 patients with MS who presented with severe spasticity to investigate safety, tolerability, and ...efficacy of oral Delta(9)-Tetrahydrocannabinol (THC) and Cannabis sativa plant extract. Both drugs were safe, but adverse events were more common with plant-extract treatment. Compared with placebo, neither THC nor plant-extract treatment reduced spasticity. Both THC and plant-extract treatment worsened the participant's global impression.
PDF
