BACKGROUND AND OBJECTIVES: Women with multiple sclerosis (MS) are at risk of disease reactivation in the early postpartum period. Ocrelizumab (OCR) is an anti-CD20 therapy highly effective at reducing MS disease activity. Data remain limited regarding use of disease-modifying therapies (DMTs), including OCR, and disease activity during peripregnancy periods. METHODS: We performed a retrospective cohort study using data from the MSBase Registry including pregnancies conceived after December 31, 2010, from women aged 18 years and older, with relapsing-remitting MS or clinically isolated syndrome. Women were classified by preconception exposure to DMTs, including OCR, rituximab (RTX), natalizumab (NAT), stratified into active (NAT-A; continued ≥28 weeks of gestation, restarted ≤1 month postpartum) or conservative (NAT-C; continued ≤4 weeks of gestation, restarted >1 month postpartum) strategies, dimethyl fumarate (DMF) or low-efficacy DMTs (interferon-beta, glatiramer acetate). Annualized relapse rates (ARRs) were calculated for 12-month prepregnancy, pregnancy, and 6-month postpartum periods. RESULTS: A total of 2,009 live births from 1,744 women were analyzed, including 73 live births from 69 women treated with preconception OCR. For OCR, no within-pregnancy relapse was observed and 3 women (4.1%) experienced 1 relapse in the postpartum period (ARR 0.09 [95% CI 0.02-0.27]). For NAT-A, 3 (3.7%) of 82 women relapsed during pregnancy (0.05 [0.01-0.15]) and 4 (4.9%) relapsed during postpartum (0.10 [0.03-0.26]). However, for NAT-C, 13 (15.9%) of 82 women relapsed within pregnancy (0.32 [0.20-0.51]) and 25 (30.5%) relapsed during postpartum (0.74 [0.50-1.06]). In the low-efficacy DMT group, 101 (7.6%) of 1,329 women experienced within-pregnancy relapse (0.12 [0.10-0.14]), followed by an increase in postpartum relapse activity with 234 women (17.6%) relapsing (0.43 [0.38-0.48]). This was similarly seen in the DMF group with 13 (7.9%) of 164 women experiencing within-pregnancy relapse (0.12 [0.06-0.20]) and 25 (15.2%) of 164 relapsing postpartum (0.39 [0.26-0.57]). Our RTX cohort had 0 of 24 women experiencing within-pregnancy relapse and 3 (12.5%) of 24 experiencing postpartum relapse. DISCUSSION: Women treated with OCR or NAT-A were observed to have low relapse rates during pregnancy and postpartum. NAT-C was associated with increased risk of relapses. There was no within-pregnancy relapse in our RTX cohort, although we caution overinterpretation due to our sample size. An effective DMT strategy with a favorable safety profile for the mother and infant should be discussed and implemented well in advance of planning a family. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for women with relapsing-remitting MS or clinically isolated syndrome who become pregnant, ocrelizumab, rituximab, and natalizumab (continued ≥28 weeks of gestation and restarted ≤1 month postpartum) were associated with reduced risk of relapses, compared with other therapeutic strategies.
- MeSH
- dospělí MeSH
- humanizované monoklonální protilátky * farmakologie aplikace a dávkování MeSH
- imunologické faktory * farmakologie aplikace a dávkování MeSH
- komplikace těhotenství * farmakoterapie MeSH
- lidé MeSH
- mladý dospělý MeSH
- poporodní období * MeSH
- registrace MeSH
- relabující-remitující roztroušená skleróza farmakoterapie MeSH
- retrospektivní studie MeSH
- roztroušená skleróza farmakoterapie MeSH
- těhotenství MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
It is unknown whether the currently known risk factors of multiple sclerosis reflect the etiology of progressive-onset multiple sclerosis (POMS) as observational studies rarely included analysis by type of onset. We designed a case-control study to examine associations between environmental factors and POMS and compared effect sizes to relapse-onset MS (ROMS), which will offer insights into the etiology of POMS and potentially contribute to prevention and intervention practice. This study utilizes data from the Primary Progressive Multiple Sclerosis (PPMS) Study and the Australian Multi-center Study of Environment and Immune Function (the AusImmune Study). This report outlines the conduct of the PPMS Study, whether the POMS sample is representative, and the planned analysis methods. The study includes 155 POMS, 204 ROMS, and 558 controls. The distributions of the POMS were largely similar to Australian POMS patients in the MSBase Study, with 54.8% female, 85.8% POMS born before 1970, mean age of onset of 41.44 ± 8.38 years old, and 67.1% living between 28.9 and 39.4° S. The POMS were representative of the Australian POMS population. There are some differences between POMS and ROMS/controls (mean age at interview: POMS 55 years vs. controls 40 years; sex: POMS 53% female vs. controls 78% female; location of residence: 14.3% of POMS at a latitude ≤ 28.9°S vs. 32.8% in controls), which will be taken into account in the analysis. We discuss the methodological issues considered in the study design, including prevalence-incidence bias, cohort effects, interview bias and recall bias, and present strategies to account for it. Associations between exposures of interest and POMS/ROMS will be presented in subsequent publications.
- MeSH
- chronicko-progresivní roztroušená skleróza * epidemiologie etiologie MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- multicentrické studie jako téma MeSH
- recidiva MeSH
- rizikové faktory MeSH
- roztroušená skleróza * epidemiologie etiologie MeSH
- studie případů a kontrol MeSH
- věk při počátku nemoci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Austrálie MeSH
BACKGROUND: Disability progression is a key milestone in the disease evolution of people with multiple sclerosis (PwMS). Prediction models of the probability of disability progression have not yet reached the level of trust needed to be adopted in the clinic. A common benchmark to assess model development in multiple sclerosis is also currently lacking. METHODS: Data of adult PwMS with a follow-up of at least three years from 146 MS centers, spread over 40 countries and collected by the MSBase consortium was used. With basic inclusion criteria for quality requirements, it represents a total of 15, 240 PwMS. External validation was performed and repeated five times to assess the significance of the results. Transparent Reporting for Individual Prognosis Or Diagnosis (TRIPOD) guidelines were followed. Confirmed disability progression after two years was predicted, with a confirmation window of six months. Only routinely collected variables were used such as the expanded disability status scale, treatment, relapse information, and MS course. To learn the probability of disability progression, state-of-the-art machine learning models were investigated. The discrimination performance of the models is evaluated with the area under the receiver operator curve (ROC-AUC) and under the precision recall curve (AUC-PR), and their calibration via the Brier score and the expected calibration error. All our preprocessing and model code are available at https://gitlab.com/edebrouwer/ms_benchmark, making this task an ideal benchmark for predicting disability progression in MS. FINDINGS: Machine learning models achieved a ROC-AUC of 0⋅71 ± 0⋅01, an AUC-PR of 0⋅26 ± 0⋅02, a Brier score of 0⋅1 ± 0⋅01 and an expected calibration error of 0⋅07 ± 0⋅04. The history of disability progression was identified as being more predictive for future disability progression than the treatment or relapses history. CONCLUSIONS: Good discrimination and calibration performance on an external validation set is achieved, using only routinely collected variables. This suggests machine-learning models can reliably inform clinicians about the future occurrence of progression and are mature for a clinical impact study.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The use of non-specific immunosuppressants (NSIS) to treat multiple sclerosis (MS) remains prevalent in certain geographies despite safety concerns, likely due to resource limitations. OBJECTIVE: To use MSBase registry data to compare real-world outcomes in adults with relapsing-remitting MS (RRMS) treated with dimethyl fumarate (DMF) or NSIS (azathioprine, cyclosporine, cyclophosphamide, methotrexate, mitoxantrone or mycophenolate mofetil) between January 1, 2014 and April 1, 2022. METHODS: Treatment outcomes were compared using inverse probability of treatment weighting (IPTW) Cox regression. Outcomes were annualized relapse rates (ARRs), time to discontinuation, time to first relapse (TTFR) and time to 24-week confirmed disability progression (CDP) or 24-week confirmed disability improvement (CDI; in patients with baseline Expanded Disability Status Scale [EDSS] score ≥2). RESULTS: After IPTW, ARR was similar for DMF (0.13) and NSIS (0.16; p = 0.29). There was no difference in TTFR between cohorts (hazard ratio [HR]: 0.98; p = 0.84). The DMF cohort experienced longer times to discontinuation (HR: 0.75; p = 0.001) and CDP (HR: 0.53; p = 0.001), and shorter time to CDI (HR: 1.99; p < 0.008), versus the NSIS cohort. CONCLUSION: This analysis supports the use of DMF to treat patients with relapsing forms of MS, and may have implications for MS practices in countries where NSIS are commonly used to treat RRMS.
- Publikační typ
- časopisecké články MeSH
IMPORTANCE: Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses. OBJECTIVES: To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab. DESIGN, SETTING, AND PARTICIPANTS: In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023. EXPOSURES: Dimethyl fumarate, fingolimod, and ocrelizumab. MAIN OUTCOMES AND MEASURES: Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method. RESULTS: Among 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab. CONCLUSION AND RELEVANCE: Study results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.
- MeSH
- dimethyl fumarát škodlivé účinky MeSH
- dospělí MeSH
- fingolimod hydrochlorid * terapeutické užití MeSH
- imunologické faktory škodlivé účinky MeSH
- imunosupresiva škodlivé účinky MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- natalizumab škodlivé účinky MeSH
- recidiva MeSH
- relabující-remitující roztroušená skleróza * farmakoterapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- pozorovací studie MeSH
WHAT IS THIS SUMMARY ABOUT?: Patient registries contain anonymous data from people who share the same medical condition. The MSBase registry contains information from over 80,000 people living with multiple sclerosis (MS) across 41 countries. Using information from the MSBase registry, the GLIMPSE (Generating Learnings In MultiPle SclErosis) study looked at real-life outcomes in 3475 people living with MS who were treated with cladribine tablets (Mavenclad®) compared with other oral treatments. WHAT WERE THE RESULTS?: Results showed that people treated with cladribine tablets stayed on treatment for longer than other treatments given by mouth. They also had fewer relapses (also called flare ups of symptoms) than people who received a different oral treatment for their MS. WHAT DO THE RESULTS MEAN?: The results provide evidence that, compared with other oral treatments for MS, cladribine tablets are an effective medicine for people living with MS.
BACKGROUND AND OBJECTIVES: Research in Multiple Sclerosis (MS) has recently focused on extracting knowledge from real-world clinical data sources. This type of data is more abundant than data produced during clinical trials and potentially more informative about real-world clinical practice. However, this comes at the cost of less curated and controlled data sets. In this work we aim to predict disability progression by optimally extracting information from longitudinal patient data in the real-world setting, with a special focus on the sporadic sampling problem. METHODS: We use machine learning methods suited for patient trajectories modeling, such as recurrent neural networks and tensor factorization. A subset of 6682 patients from the MSBase registry is used. RESULTS: We can predict disability progression of patients in a two-year horizon with an ROC-AUC of 0.85, which represents a 32% decrease in the ranking pair error (1-AUC) compared to reference methods using static clinical features. CONCLUSIONS: Compared to the models available in the literature, this work uses the most complete patient history for MS disease progression prediction and represents a step forward towards AI-assisted precision medicine in MS.
- MeSH
- lidé MeSH
- neuronové sítě (počítačové) MeSH
- roztroušená skleróza * MeSH
- strojové učení * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
