Author Of 5 Presentations
P0151 - Serum contactin-1 levels as a biomarker of long-term disease progression in natalizumab-treated multiple sclerosis. (ID 1674)
Abstract
Background
Contactin-1 (CNTN1) is a protein that is expressed in paranodal axonal domains and involved in myelin formation in the central nervous system (CNS) by way of axo-glia interaction, which is affected in multiple sclerosis (MS). Studying patients under natalizumab treatment provides a model to investigate correlations of novel biomarkers with non-inflammation induced disease progression in MS.
Objectives
To investigate longitudinal serum CNTN1 in relation to clinical and radiological disease activity and progression independent of inflammatory disease activity in relapsing-remitting MS (RRMS).
Methods
Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were selected from an ongoing observational cohort study. Serum CNTN1 was analyzed at baseline before natalizumab initiation, and at 3, 12, 24 months and last follow-up. Clinical and radiological characteristics and CNTN1 levels were compared between patients with either progressive, stable or improved disability according to ‘EDSS plus’ criteria: Expanded Disability Status Scale (EDSS), 9-hole peg test (9HPT) and timed 25-foot walk test (T25W) combined. A significant change in at least one assessment was defined as progression (increase) or improvement (decrease), and no significant changes in any assessment as stability.
Results
Forty-three subjects (48%) showed disability progression on EDSS plus between reference and last follow-up visit, 34 (38%) remained stable and 12 (13%) improved (median [interquartile range (IQR)] follow-up 5.2 [4.3-6.7] years). No statistically significant differences were found in the proportion of patients with clinical and radiological evidence of disease activity 1 year prior to baseline or during follow-up. Baseline serum CNTN1 (median [IQR], pg/mL) was significantly lower in the group with progressive disability (920 [798-1283]) compared to patients with either stable (1169 [861-1367] p=0.043) or improved disability (1133 [1046-1378], p=0.031). A 100 pg/ml increase in baseline CNTN1 was consistent with an odds ratio [95% confidence interval] of 0.809 [0.684-0.958] (p=0.014) for disability progression. Longitudinal serum CNTN1 levels remained consistently lower in the group with progressive disability compared to the non-progressive group (stable and improved group together).
Conclusions
Long-term disability progression in MS patients treated with natalizumab was associated with lower serum CNTN1 concentrations compared to patients with either stable or improved disability.
P0398 - Switching from natalizumab to ocrelizumab in patients with relapsing-remitting multiple sclerosis. (ID 1725)
Abstract
Background
Ocrelizumab (OCR) is an alternative therapy for relapsing-remitting multiple sclerosis (RRMS) patients with an increased risk of natalizumab (NTZ) associated progressive multifocal leukoencephalopathy (PML). We developed a switch protocol for PML surveillance and prevention of rebound disease activity.
Objectives
To evaluate clinical, radiological and biochemical markers in patients switching from NTZ to OCR using the locally developed switch protocol of the MS Center Amsterdam.
Methods
All patients with previous NTZ and current OCR treatment were selected from an ongoing observational cohort study with regular collection of blood samples in the Amsterdam University Medical Center (UMC) MS Biobank. Reasons for therapy switch were discriminated between patients with (indirect switchers) and without (direct switchers) use of other disease modifying treatment (DMT) during interval. Clinical, biochemical and radiological endpoints were prospectively collected from first NTZ to last OCR infusion. Serum neurofilament light (sNfL) was analyzed in direct switchers, using baseline and last follow-up samples during NTZ treatment and samples taken before every OCR infusion.
Results
Forty-one patients with current OCR and previous NTZ treatment were included with a median follow-up of 7.7 years. Twenty-eight patients switched directly, of which 21 due to PML risk. Three direct switchers suffered from a relapse, of which 1 patient showed evidence of disease activity on brain Magnetic Resonance Imaging (MRI). Two other male patients were diagnosed with carry-over PML with favorable outcomes. Before OCR became available, 13 patients switched from NTZ to other DMT due to PML risk but eventually escalated to OCR because of disease activity, progression or adverse events. Among these indirect switchers, 4 patients showed evidence of clinical or radiological disease activity. Excluding carry-over PML, OCR treatment maintained or established complete disease activity suppression in 84% of patients. Clinical measures of disability showed no significant changes. Mean sNfL significantly decreased during NTZ treatment and remained stable during OCR treatment.
Conclusions
A stringent protocol can contribute to an effective switch from NTZ to OCR in RRMS. In this observational cohort study of direct and indirect switchers, disease activity suppression was maintained or established in 84% with concurrent stability of clinical measures and sNfL.
P0445 - Cohort description of Project Y: Searching for the cause of phenotype diversity in MS (ID 1352)
Abstract
Background
Detecting factors that influence disease variability in MS patients is crucial to provide novel insights into the etiology of the disease and guide the search for effective therapies. To study the phenotypic variability, well-defined unbiased cohort studies are necessary. The most common and arguably most important variable to be considered as a confounding factor when studying variability of disease course in MS, is age.
Objectives
To identify determinants that explain phenotypic variability in MS, while eliminating the undesirable effect of age variation between MS patients.
Methods
Project Y is an ongoing population-based cross-sectional study of all people with MS born in the Netherlands in 1966. Participants are subjected to extensive examinations of a wide array of potential determinants and outcome measures: functional and static imaging, biomarkers in body fluid, physical and cognitive measurements, and lifestyle factors early and later in life. Age and sex matched controls are included.
Results
As for July 2020, a total of 386 eligible MS patients were identified, of which 31 refused to participate and 86 patients awaiting inclusion. Thirteen patients had passed away prior to study inclusion. Between December 2017 and July 2020, 269 MS patients participated with either a full or partial data collection, together with 125 healthy controls. The total number of identified cases (386) results in a prevalence of at least 1.7/1000 in the birth year 1966.
Conclusions
The first preliminary data of our unique cohort indicate that the previously presumed prevalence of MS in the Netherlands (1/1000) is a serious underestimation of the actual prevalence.
P0481 - Natalizumab discontinuation in a Dutch real-world cohort (ID 1754)
Abstract
Background
Natalizumab is a widely used treatment option for patients with relapsing-remitting multiple sclerosis (RRMS). Identifying characteristics of patients discontinuing natalizumab treatment and reasons for discontinuation could help improve clinical decision making regarding natalizumab treatment in multiple sclerosis (MS).
Objectives
To determine characteristics of RRMS patients that discontinued natalizumab treatment in a Dutch real-world cohort.
Methods
Data were collected from an ongoing observational cohort study of all natalizumab treated patients in the Amsterdam UMC. Standard clinical parameters, total number of natalizumab infusions, reasons for discontinuation and therapies the patients switched to after discontinuation of natalizumab were collected.
Results
254 patients have ever received natalizumab treatment in our cohort, of which 148 patients stopped treatment. Mean age at discontinuation of natalizumab was 40.2 years, and 65.8% was female. Patients received an average of 68 infusions. Median treatment duration with natalizumab was 4.77 years. Mean Expanded Disablity Status Scale (EDSS) was similar at the start and stop of natalizumab treatment. The majority of patients (109 in total (73.6%)) stopped natalizumab treatment solely due to JC virus (JCV) positivity. Eight patients (5.4%) discontinued due to progression of MS, 3 (2.0%) due to pregnancy, 12 (8.1%) due to an allergic reaction or antibodies, 2 (1.4%) due to side effects, 4 (2.7%) due to the patients preference for another therapy, 3 (2.0%) due to clinical stabilisation and the remaining 7 patients (4.7%) due to other reasons. Most patients switched to another type of disease modifying therapy (DMT) after natalizumab discontinuation. Patients most frequently switched to fingolimod (76 patients (51.4%)) or ocrelizumab (26 patients (17.6%)) after discontinuation of natalizumab. Fourteen patients (9.5%) did not start another DMT after natalizumab discontinuation. Thirty-nine patients (26.4%) switched a second time to a different DMT and 19 patients (12.8%) stopped DMT after an initial switch.
Conclusions
Our results suggest JCV positivity to be the most frequent reason for natalizumab discontinuation. The heterogeneity in treatment switches suggests individual treatment plans are frequently present in MS. Recognising reasons for treatment discontinuation and treatment decisions made in our patient cohort can be helpful in future clinical decision making.
P0881 - “Mild disease course of carry-over progressive multifocal leukoencephalopathy after switching from natalizumab to ocrelizumab” (ID 1406)
Abstract
Background
Natalizumab is an effective disease modifying therapy (DMT) for relapsing remitting multiple sclerosis (RRMS). However, it is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Nine confirmed cases of PML have been reported in patients using ocrelizumab, another effective DMT for MS. In 8 cases, patients previously used natalizumab or fingolimod, likely causing PML. This phenomenon has been described as carry-over PML.
Objectives
To describe the disease course of carry-over PML after switching from natalizumab to ocrelizumab in two patients with RRMS.
Methods
Two case reports with 1 year of follow-up and retrospective longitudinal measurements of serum neurofilament light (sNfL) levels and B-cell count. Both patients provided informed consent.
Results
Regular follow-up showed no disease activity under natalizumab treatment and both patients switched to ocrelizumab following a stringent safety protocol including two additional MRI brain scans and cerebrospinal fluid (CSF) analysis. Both patients received a single infusion of 300 mg ocrelizumab before PML diagnosis. PML was diagnosed ±11 weeks (case 1) and ±13 weeks (case 2) after the last natalizumab infusion. At that time, both patients were asymptomatic. In retrospect, subtle signs suggestive of PML were already present on MRI under natalizumab treatment. One patient developed PML despite extended interval dosing of natalizumab. Both patients developed mild immune reconstitution inflammatory syndrome (IRIS) despite complete B-cell depletion. SNfL levels were 9.9 pg/ml (reference range 1-15 pg/ml) for case 1 and 16.7 pg/ml (reference range 2-18 pg/ml) for case 2 at the time of PML diagnosis and increased to 15.0 pg/ml and 36.5 pg/mL during PML-IRIS. SNfL was not elevated before radiological diagnosis of PML. PML-IRIS lesions stabilized after treatment with mefloquine and mirtazapine followed by methylprednisolone with sNfL levels of 9.0 pg/mL and 12.3 pg/mL, respectively. One patient reported no clinical symptoms and one patient only mild clinical symptoms with full recovery during the disease course of PML-IRIS. Both patients continued with ocrelizumab when B-cells started to repopulate ±10 months after the first ocrelizumab infusion.
Conclusions
The clinical course of carry-over PML was mild in both patients, suggesting that B-cell depletion did not aggravate PML-IRIS in these two patients.
Presenter Of 2 Presentations
P0151 - Serum contactin-1 levels as a biomarker of long-term disease progression in natalizumab-treated multiple sclerosis. (ID 1674)
Abstract
Background
Contactin-1 (CNTN1) is a protein that is expressed in paranodal axonal domains and involved in myelin formation in the central nervous system (CNS) by way of axo-glia interaction, which is affected in multiple sclerosis (MS). Studying patients under natalizumab treatment provides a model to investigate correlations of novel biomarkers with non-inflammation induced disease progression in MS.
Objectives
To investigate longitudinal serum CNTN1 in relation to clinical and radiological disease activity and progression independent of inflammatory disease activity in relapsing-remitting MS (RRMS).
Methods
Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were selected from an ongoing observational cohort study. Serum CNTN1 was analyzed at baseline before natalizumab initiation, and at 3, 12, 24 months and last follow-up. Clinical and radiological characteristics and CNTN1 levels were compared between patients with either progressive, stable or improved disability according to ‘EDSS plus’ criteria: Expanded Disability Status Scale (EDSS), 9-hole peg test (9HPT) and timed 25-foot walk test (T25W) combined. A significant change in at least one assessment was defined as progression (increase) or improvement (decrease), and no significant changes in any assessment as stability.
Results
Forty-three subjects (48%) showed disability progression on EDSS plus between reference and last follow-up visit, 34 (38%) remained stable and 12 (13%) improved (median [interquartile range (IQR)] follow-up 5.2 [4.3-6.7] years). No statistically significant differences were found in the proportion of patients with clinical and radiological evidence of disease activity 1 year prior to baseline or during follow-up. Baseline serum CNTN1 (median [IQR], pg/mL) was significantly lower in the group with progressive disability (920 [798-1283]) compared to patients with either stable (1169 [861-1367] p=0.043) or improved disability (1133 [1046-1378], p=0.031). A 100 pg/ml increase in baseline CNTN1 was consistent with an odds ratio [95% confidence interval] of 0.809 [0.684-0.958] (p=0.014) for disability progression. Longitudinal serum CNTN1 levels remained consistently lower in the group with progressive disability compared to the non-progressive group (stable and improved group together).
Conclusions
Long-term disability progression in MS patients treated with natalizumab was associated with lower serum CNTN1 concentrations compared to patients with either stable or improved disability.
P0398 - Switching from natalizumab to ocrelizumab in patients with relapsing-remitting multiple sclerosis. (ID 1725)
Abstract
Background
Ocrelizumab (OCR) is an alternative therapy for relapsing-remitting multiple sclerosis (RRMS) patients with an increased risk of natalizumab (NTZ) associated progressive multifocal leukoencephalopathy (PML). We developed a switch protocol for PML surveillance and prevention of rebound disease activity.
Objectives
To evaluate clinical, radiological and biochemical markers in patients switching from NTZ to OCR using the locally developed switch protocol of the MS Center Amsterdam.
Methods
All patients with previous NTZ and current OCR treatment were selected from an ongoing observational cohort study with regular collection of blood samples in the Amsterdam University Medical Center (UMC) MS Biobank. Reasons for therapy switch were discriminated between patients with (indirect switchers) and without (direct switchers) use of other disease modifying treatment (DMT) during interval. Clinical, biochemical and radiological endpoints were prospectively collected from first NTZ to last OCR infusion. Serum neurofilament light (sNfL) was analyzed in direct switchers, using baseline and last follow-up samples during NTZ treatment and samples taken before every OCR infusion.
Results
Forty-one patients with current OCR and previous NTZ treatment were included with a median follow-up of 7.7 years. Twenty-eight patients switched directly, of which 21 due to PML risk. Three direct switchers suffered from a relapse, of which 1 patient showed evidence of disease activity on brain Magnetic Resonance Imaging (MRI). Two other male patients were diagnosed with carry-over PML with favorable outcomes. Before OCR became available, 13 patients switched from NTZ to other DMT due to PML risk but eventually escalated to OCR because of disease activity, progression or adverse events. Among these indirect switchers, 4 patients showed evidence of clinical or radiological disease activity. Excluding carry-over PML, OCR treatment maintained or established complete disease activity suppression in 84% of patients. Clinical measures of disability showed no significant changes. Mean sNfL significantly decreased during NTZ treatment and remained stable during OCR treatment.
Conclusions
A stringent protocol can contribute to an effective switch from NTZ to OCR in RRMS. In this observational cohort study of direct and indirect switchers, disease activity suppression was maintained or established in 84% with concurrent stability of clinical measures and sNfL.