Effects of Natalizumab and Fingolimod on Clinical, Cognitive, and Magnetic Resonance Imaging Measures in Multiple Sclerosis.
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ABSTRACT:
SUBMITTER: Preziosa P
PROVIDER: S-EPMC7007466 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Effects of Natalizumab and Fingolimod on Clinical, Cognitive, and Magnetic Resonance Imaging Measures in Multiple Sclerosis.
Preziosa Paolo P Rocca Maria A MA Riccitelli Gianna C GC Moiola Lucia L Storelli Loredana L Rodegher Mariaemma M Comi Giancarlo G Signori Alessio A Falini Andrea A Filippi Massimo M
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20200101 1
Studies comparing the effects of natalizumab and fingolimod in relapsing-remitting multiple sclerosis (RRMS) are limited. We aimed to compare natalizumab and fingolimod effects on clinical, neuropsychological, and MRI measures in RRMS patients after 2 years of treatment. RRMS patients starting natalizumab (n = 30) or fingolimod (n = 25) underwent neurologic, neuropsychological, and brain MRI assessments at baseline, month (M) 6, M12, and M24. Volumes of lesions, brain, gray matter (GM), white ma ...[more]
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Project description:Fingolimod and natalizumab are approved disease-modifying drugs in relapsing-remitting multiple sclerosis (RRMS). The two drugs have different modes of action and may therefore influence different aspects of MS-related tissue damage. In this retrospective cohort study, we longitudinally compared patients treated with fingolimod and patients treated with natalizumab by measures based on structural magnetic resonance imaging (MRI). We included patients with RRMS given that two standardized MRI scans under the same drug were available with an interval of at least 6 months both from therapy start to baseline scan and from baseline scan to follow-up scan. After matching for age, baseline and follow-up scans from 93 patients (fingolimod, 48; natalizumab, 45) were investigated. Mean follow-up time was 1.9 years. We determined the number of new white matter lesions as well as thalamic, cortical, and whole-brain atrophy. After scaling for time of the interscan interval, measures were analyzed by group comparisons and, to account for demographic and clinical characteristics, by multiple regression models and a binary logistic regression model. Compared to natalizumab, fingolimod treatment went along with more new white matter lesions (median [interquartile range, IQR] 0.0 [0.0; 0.7] vs. 0.0 [0.0; 0.0] /year; p < 0.01) whereas whole-brain atrophy was lower (median [IQR] 0.2 [0.0; 0.5] vs. 0.5 [0.2; 1.0] %/year; p = 0.01). These significant differences were confirmed by multiple regression models and the binary logistic regression model. In conclusion, our observation is compatible with stronger neuroprotective properties of fingolimod compared to natalizumab.
| S-EPMC8804113 | biostudies-literature
Project description:Natalizumab and fingolimod are effective multiple sclerosis (MS) therapies that disrupt lymphocyte migration but have differential effects on B cell maturation and trafficking. We investigated their effects on peripheral blood (PB) and cerebrospinal fluid (CSF) B cell repertoires using next-generation deep sequencing. Paired CSF and PB B cell subsets (naïve, CD27+ memory, and CD27-IgD- double-negative B cells and plasmablasts) were collected by applying flow cytometry at baseline and after 6 months of treatment and their respective heavy-chain variable region repertoires assessed by Illumina MiSeq. Treatment with fingolimod contracted, whereas natalizumab expanded circulating PB B cells. CSF B cell numbers remained stable following fingolimod treatment but decreased with natalizumab therapy. Clonal overlap between CSF and PB B cells was reduced with natalizumab treatment but remained stable with fingolimod therapy. Lineage analyses of pre- and posttreatment CSF B cell repertoires revealed large, clonally expanded B cell clusters in natalizumab-treated MS patients but no intrathecal clonal expansion following fingolimod therapy. Our findings suggest that natalizumab diminishes the exchange of peripheral and intrathecal B cells without impacting intrathecal clonal expansion. In contrast, fingolimod treatment fails to alter blood-brain barrier B cell exchange but diminishes intrathecal clonal expansion. Sphingosine-1 phosphate receptor inhibition may alter intrathecal B cell biology in MS.
| S-EPMC8116403 | biostudies-literature
Project description:ObjectiveTo compare 2-year effectiveness and discontinuation of natalizumab (NTZ) versus fingolimod (FTY) and dimethyl fumarate (DMF) in the treatment of multiple sclerosis (MS).MethodsPatients prescribed NTZ, FTY, or DMF at the Rocky Mountain MS Center at University of Colorado were identified. Clinician-reported data were retrospectively collected. Outcomes include a composite effectiveness measure consisting of new T2 lesion, gadolinium-enhancing lesion, and/or clinical relapse, individual effectiveness outcomes and discontinuation over 2 years. Logistic regression was used for data analysis on patients matched by propensity scores and using ATT doubly robust weighting estimator.ResultsA total of 451, 271, and 342 patients were evaluated on NTZ, FTY, and DMF over 2 years, respectively. Patients had a mean age of 39.8 (NTZ), 42.5(FTY), and 45.8 (DMF) years; were predominantly female (76.7% NTZ; 72.0% FTY; 69.6% DMF); and had a mean MS disease duration of 11-12 years for all groups. At ≤24 months, 22.2%, 34.7%, and 33.6% experienced a new T2 lesion, gadolinium-enhancing lesion, and/or clinical relapse on NTZ, FTY, and DMF, respectively. Using ATT doubly robust weighting estimator, FTY versus NTZ and DMF versus NTZ had an odds ratio of 2.00 (95%CI:[1.41-2.85], P < 0.001) and 2.38 [95% CI: 1.68-3.37], P < 0.001) respectively, for experiencing a new T2 lesion, gadolinium enhancing lesion, and/or clinical relapse. At ≤24 months, 32.6%, 34.3%, and 47.1% discontinued NTZ, FTY, and DMF, respectively. The majority of discontinuations were due to becoming JCV positive(12.6%) for NTZ and due to adverse events for both FTY(17%) and DMF(24.0%).InterpretationNTZ appears to be more effective and tolerable than FTY and DMF.
| S-EPMC6389745 | biostudies-literature
Project description:IntroductionLimited comparative effectiveness data for rituximab (RTX) versus natalizumab (NTZ), fingolimod (FTY), and dimethyl fumarate (DMF) for the treatment of multiple sclerosis (MS) exist.MethodsClinician-reported data on patients prescribed RTX, NTZ, FTY, or DMF for the treatment of MS at the Rocky Mountain MS Center at the University of Colorado were retrospectively collected. Outcomes included a composite effectiveness measure consisting of clinical relapse, contrast-enhancing lesions, and/or new T2 lesions, individual effectiveness outcomes, and discontinuation. Logistic regression was used on patients matched by propensity scores and using average treatment effect on treated doubly robust weighting estimator.ResultsA total of 182, 451, 271, and 342 patients initiated RTX, NTZ, FTY, and DMF and were followed for 2 years. Before and after adjustment, the odds of experiencing disease activity was significantly higher for FTY [adjusted OR (aOR) = 3.17 (95% CI: 1.81-5.55), P < 0.001].and DMF [aOR = 2.68 (95% CI:1.67-4.29), P < 0.001], and similar for NTZ [aOR = 1.36 (95% CI:0.83-2.23), P = 0.216] versus RTX. When examining months 6-24, NTZ demonstrated higher odds of disease activity compared to RTX [aOR = 2.21 (95% CI: 1.20-4.06), P = 0.007]. Similar odds of discontinuation were seen between NTZ and RTX [aOR = 1.39 (95% CI: 0.88-2.20), P = 0.157]; however, FTY [aOR = 2.02 (95% CI: 1.24-3.30), P = 0.005] and DMF [aOR = 3.27 (95% CI: 2.15-4.97), P < 0.001] had greater odds of discontinuation than RTX.InterpretationRTX demonstrated superior effectiveness and discontinuation outcomes compared to FTY and DMF. Although RTX demonstrated similar effectiveness and discontinuation compared to NTZ, RTX had superior effectiveness during months 6-24 and fewer discontinuations when excluding discontinuations due to insurance issues. Results suggest superiority of RTX in reducing disease activity and maintaining long-term treatment in a real-world MS cohort.
| S-EPMC7480919 | biostudies-literature
Project description:BackgroundMagnetic resonance imaging (MRI) provides insight into various pathological processes in multiple sclerosis (MS) and may provide insight into patterns of damage among patients.ObjectiveWe sought to determine if MRI features have clinical discriminative power among a cohort of MS patients.MethodsNinety-six relapsing remitting and seven progressive MS patients underwent myelin water fraction (MWF) imaging and conventional MRI for cortical thickness and thalamic volume. Patients were clustered based on lesion level MRI features using an agglomerative hierarchical clustering algorithm based on principal component analysis (PCA).ResultsOne hundred and three patients with 1689 MS lesions were analyzed. PCA on MRI features demonstrated that lesion MWF and volume distributions (characterized by 25th, 50th, and 75th percentiles) accounted for 87% of the total variability based on four principal components. The best hierarchical cluster confirmed two distinct patient clusters. The clustering features in order of importance were lesion median MWF, MWF 25th, MWF 75th, volume 75th percentiles, median individual lesion volume, total lesion volume, cortical thickness, and thalamic volume (all p values <0.01368). The clusters were associated with patient Expanded Disability Status Scale (EDSS) (n = 103, p = 0.0338) at baseline and at 5 years (n = 72, p = 0.0337).ConclusionsThese results demonstrate that individual MRI features can identify two patient clusters driven by lesion-based values, and our unique approach is an analysis blinded to clinical variables. The two distinct clusters exhibit MWF differences, most likely representing individual remyelination capabilities among different patient groups. These findings support the concept of patient-specific pathophysiological processes and may guide future therapeutic approaches.
| S-EPMC8727028 | biostudies-literature
Project description:There is a lack of knowledge about the evolution of cerebrospinal fluid (CSF) markers in multiple sclerosis (MS) patients undergoing natalizumab treatment. We aimed to evaluate the effect of natalizumab on basic inflammatory CSF and MRI measures. Together, 411 patients were screened for eligibility and 93 subjects with ≥2 CSF examinations ≤6 months before and ≥12 months after natalizumab initiation were recruited. The effect of natalizumab on CSF as well as clinical and paraclinical measures was analyzed using adjusted mixed models. Natalizumab induced a decrease in CSF leukocytes (p < 1 × 10-15), CSF protein (p = 0.00007), the albumin quotient (p = 0.007), the IgG quotient (p = 6 × 10-15), the IgM quotient (p = 0.0002), the IgG index (p = 0.0004), the IgM index (p = 0.003) and the number of CSF-restricted oligoclonal bands (OCBs) (p = 0.0005). CSF-restricted OCBs positivity dropped from 94.6% to 86% but 26 patients (28%) had an increased number of OCBs at the follow-up. The baseline to follow-up EDSS and T2-LV were stable; a decrease in the relapse rate was consistent with a decrease in the CSF inflammatory markers and previous knowledge about the effectiveness of natalizumab. The average annualized brain volume loss during the follow-up was -0.50% (IQR = -0.96, -0.16) and was predicted by the baseline IgM index (B = -0.37; p = 0.003). Natalizumab is associated with a reduction of basic CSF inflammatory measures supporting its strong anti-inflammatory properties. The IgM index at the baseline predicted future brain volume loss during the course of natalizumab treatment.
| S-EPMC8699923 | biostudies-literature
Project description:Conventional magnetic resonance imaging (MRI) methods do not quantify the severity of multiple sclerosis (MS) white matter lesions or measure pathology within normal-appearing white matter (NAWM).Gradient Echo Plural Contrast Imaging (GEPCI), a fast MRI technique producing inherently co-registered images for qualitative and quantitative assessment of MS, was used to 1) correlate with disability; 2) distinguish clinical MS subtypes; 3) determine prevalence of veins co-localized within lesions in WM.Thirty subjects representing relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS) subtypes were scanned with clinical and GEPCI protocols. Standard measures of physical disability and cognition were correlated with magnetic resonance metrics. Lesions with central veins were counted for RRMS subjects.Tissue damage load (TDL-GEPCI) and lesion load (LL-GEPCI) derived with GEPCI correlated better with MS functional composite (MSFC) measures and most other neurologic measures than lesion load derived with FLAIR (LL-FLAIR). GEPCI correctly classified clinical subtypes in 70% subjects. A central vein could be identified in 76% of WM lesions in RRMS subjects on GEPCI T2*-SWI images.GEPCI lesion metrics correlated better with neurologic disability than lesion load derived using FLAIR imaging, and showed promise in classifying clinical subtypes of MS. These improvements are likely attributable to the ability of GEPCI to quantify tissue damage.
| S-EPMC4366944 | biostudies-literature
Project description:ImportanceAs disease-modifying treatment options for multiple sclerosis increase, comparisons of the options based on real-world evidence may guide clinical decision-making.ObjectiveTo compare the relapse outcomes between 2 pairs of disease-modifying treatments: dimethyl fumarate vs fingolimod and natalizumab vs rituximab.Design, setting, and participantsThis comparative effectiveness study integrated data from a clinic-based multiple sclerosis research registry and its linked electronic health records (EHR) system between January 1, 2006, and December 31, 2016, and built treatment groups for each pairwise disease-modifying treatment comparison according to both registry records and electronic prescriptions. Parallel analyses were conducted from October 11, 2019, to July 7, 2021.Main outcomes and measuresThe main outcomes were the 1-year and 2-year relapse rates as well as the time to relapse. To compare relapse outcomes, the study adjusted for covariates from 2 sources (registry and EHR) and corrected for confounding biases among the covariates by the doubly robust estimation.ResultsThe study included 4 treatment groups: dimethyl fumarate (n = 260; 198 women [76.2%]; 227 non-Hispanic White individuals [87.3%]; mean [SD] age at diagnosis, 41.7 [10.4] years), fingolimod (n = 267; 190 women [71.2%]; 222 non-Hispanic White individuals [83.1%]; mean [SD] age at diagnosis, 37.9 [9.9] years), natalizumab (n = 204; 160 women [78.4%]; 172 non-Hispanic White individuals [84.3%]; mean [SD] age at diagnosis, 37.2 [10.6] years), and rituximab (n = 115; 83 women [72.2%]; 99 non-Hispanic White individuals [86.1%]; mean [SD] age at diagnosis, 44.1 [11.1] years). No significant differences were found in the relapse outcomes between dimethyl fumarate and fingolimod after correcting for confounding biases and multiple testing (difference in 1-year relapse rate, 0.028 [95% CI, -0.031 to 0.084]; difference in 2-year relapse rate, 0.071 [95% CI, 0.008-0.128]; relative risk of 2-year non-relapse, 0.957 [95% CI, 0.884-1.035] with dimethyl fumarate as reference). When compared with rituximab, natalizumab was associated with a higher relapse rate for all 3 outcomes after bias correction and multiple testing (difference in 1-year relapse rate, 0.080 [95% CI, 0.013-0.137]; difference in 2-year relapse rate, 0.132 [95% CI, 0.043-0.189]; relative risk of 2-year non-relapse, 0.903 [95% CI, 0.822-0.944]). Confounders were identified from EHR data not recorded in the registry data through data-driven feature selection.Conclusions and relevanceThis study reports real-world evidence of equivalent relapse outcomes between dimethyl fumarate and fingolimod and relapse reduction in favor of rituximab relative to natalizumab. This approach illustrates the value of incorporating EHR data as high-dimensional covariates in real-world treatment comparison.
| S-EPMC8596196 | biostudies-literature
Project description:ImportanceAlthough highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden.ObjectiveTo examine the risk of serious infections associated with disease-modifying treatments for MS.Design, setting, and participantsThis nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included.ExposuresTreatment with rituximab, natalizumab, fingolimod, and interferon beta and GA.Main outcomes and measuresSerious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions.ResultsA total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]).Conclusions and relevancePatients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.
| S-EPMC6784753 | biostudies-literature
Project description:Magnetic resonance imaging (MRI) is a fundamental tool in the diagnosis and management of neurological diseases such as multiple sclerosis (MS). New portable, low-field strength, MRI scanners could potentially lower financial and technical barriers to neuroimaging and reach underserved or disabled populations, but the sensitivity of these devices for MS lesions is unknown. We sought to determine if white matter lesions can be detected on a portable 64mT scanner, compare automated lesion segmentations and total lesion volume between paired 3T and 64mT scans, identify features that contribute to lesion detection accuracy, and explore super-resolution imaging at low-field. In this prospective, cross-sectional study, same-day brain MRI (FLAIR, T1w, and T2w) scans were collected from 36 adults (32 women; mean age, 50 ± 14 years) with known or suspected MS using Siemens 3T (FLAIR: 1 mm isotropic, T1w: 1 mm isotropic, and T2w: 0.34-0.5 × 0.34-0.5 × 3-5 mm) and Hyperfine 64mT (FLAIR: 1.6 × 1.6 × 5 mm, T1w: 1.5 × 1.5 × 5 mm, and T2w: 1.5 × 1.5 × 5 mm) scanners at two centers. Images were reviewed by neuroradiologists. MS lesions were measured manually and segmented using an automated algorithm. Statistical analyses assessed accuracy and variability of segmentations across scanners and systematic scanner biases in automated volumetric measurements. Lesions were identified on 64mT scans in 94% (31/33) of patients with confirmed MS. The average smallest lesions manually detected were 5.7 ± 1.3 mm in maximum diameter at 64mT vs 2.1 ± 0.6 mm at 3T, approaching the spatial resolution of the respective scanner sequences (3T: 1 mm, 64mT: 5 mm slice thickness). Automated lesion volume estimates were highly correlated between 3T and 64mT scans (r = 0.89, p < 0.001). Bland-Altman analysis identified bias in 64mT segmentations (mean = 1.6 ml, standard error = 5.2 ml, limits of agreement = -19.0-15.9 ml), which over-estimated low lesion volume and under-estimated high volume (r = 0.74, p < 0.001). Visual inspection revealed over-segmentation was driven venous hyperintensities on 64mT T2-FLAIR. Lesion size drove segmentation accuracy, with 93% of lesions > 1.0 ml and all lesions > 1.5 ml being detected. Using multi-acquisition volume averaging, we were able to generate 1.6 mm isotropic images on the 64mT device. Overall, our results demonstrate that in established MS, a portable 64mT MRI scanner can identify white matter lesions, and that automated estimates of total lesion volume correlate with measurements from 3T scans.
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