Hospital Universitario Donostia
Department of Neurology

Author Of 1 Presentation

Gender Differences, Hormones and Sex Chromosomes Oral Presentation

PS12.04 - Pregnancy in a modern day multiple sclerosis cohort: Predictors of relapse during pregnancy

Abstract

Background

Historically, disease activity diminished during pregnancy in women with relapsing-remitting MS. Today, women with high disease activity are more likely to attempt pregnancy due to the disease control that new therapies offer. But disease activity during pregnancy in the modern day remains understudied.

Objectives

Describe disease activity in a modern pregnancy cohort, grouped by preconception disease-modifying therapy (DMT) class; determine the predictors of relapse during pregnancy.

Methods

Data were obtained from the MSBase Registry. Term/preterm pregnancies conceived from 2011-2019 were included. DMT were classed by low, moderate and high-efficacy. Annualized relapse rates (ARR) were calculated for each pregnancy trimester and 12 months either side. Predictors of relapse during pregnancy were determined using clustered logistic regression.

Results

We included 1640 pregnancies from 1452 women. DMT used in the year before conception were none (n=346), low (n=845), moderate (n=207) and high-efficacy (n=242). Most common DMT in each class was interferon-beta (n=597), fingolimod (n=147) and natalizumab (n=219) for low, moderate and high-efficacy respectively. Conception EDSS ≥2 was more common in higher efficacy DMT groups (high: 41.3%; moderate 28.5%; low 22.4%; none 20.2%). For low-efficacy and no DMT groups, ARR fell through pregnancy. ARR of the moderate-efficacy group increased in the 1st pregnancy trimester (0.55 [95% CI 0.36-0.80] vs 0.14 [95% CI 0.10-0.21] on low-efficacy), then decreased to a trough in the third. Conversely, ARR steadily increased throughout pregnancy for those on high-efficacy DMT (3rd trimester: 0.42 [95% CI 0.25-0.66] vs 0.12 [95% CI 0.07-0.19] on low-efficacy). Higher efficacy DMT groups were associated with higher ARR in the early postpartum period (high: 0.84 [95% CI 0.62-1.1]; moderate: 0.90 [95% CI 0.65-1.2]; low: 0.47 [95% CI 0.38-0.58]). Preconception use of high and moderate-efficacy DMT and higher preconception ARR were predictors of relapse in pregnancy. But, continuation of high-efficacy DMT into pregnancy was protective against relapse (odds ratio 0.80 [95% CI 0.68-0.94]). Age ≥35 years was associated with reduced odds of relapse.

Conclusions

Women with RRMS treated with moderate or high-efficacy DMT are at greater risk of relapse during pregnancy. Careful pregnancy management, and use of long-acting high-efficacy DMT preconception, or continuing natalizumab into pregnancy, may prevent relapse in pregnancy.

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Author Of 5 Presentations

Biostatistical Methods Poster Presentation

P0018 - Variability of the response to immunotherapy among sub-groups of patients with multiple sclerosis (ID 1239)

Abstract

Background

Our current understanding of demographic and clinical modifiers of the effectiveness of multiple sclerosis (MS) therapies is limited.

Objectives

To assess whether patients’ response to disease modifying therapies (DMT) in MS varies by disease activity (annualised relapse rate, presence of new MRI lesions), disability, age, MS duration or disease phenotype.

Methods

Using the international MSBase registry, we selected patients with MS followed for ≥1 year, with ≥3 visits, ≥1 visit per year. Marginal structural models (MSMs) were used to compare the hazard ratios (HR) of 6-month confirmed worsening and improvement of disability (EDSS), and the incidence of relapses between treated and untreated periods. MSMs were continuously re-adjusted for patient age, sex, pregnancy, date, time from first symptom, prior relapse history, disability and MRI activity.

Results

Among 23 687 patients with relapsing MS, those on DMT experienced 20% greater chance of disability improvement [HR 1.20 (95% CI 1.0-1.5)], 47% lower risk of disability worsening [HR 0.53 (0.39-0.71)] and 51% reduction in relapses [HR 0.49 (0.43-0.55)]. The effect of DMT on relapses and EDSS worsening was attenuated with longer MS duration and higher prior relapse rate. The effect of DMT on EDSS improvement and relapses was more evident in low EDSS categories. DMT was associated with 51% EDSS improvement in patients without new MRI lesions [HR 1.51 (1.00-2.28)] compared to 4% in those with MRI activity [HR 1.04 (0.88-1.24)]. Among 26329 participants with relapsing or progressive MS, DMT was associated with 25% reduction in EDSS worsening and 42% reduction in relapses in patients with relapsing MS [HR 0.75 (0.65-0.86) and HR 0.58 (CI 0.54-62), respectively], while evidence for such beneficial effects of treatment in patients with progressive MS was not found [HR 1.11 (0.91-1.46) and HR 1.16 (0.91-1.46), respectively].

Conclusions

DMTs are associated with reduction in relapse frequency, progression of disability, and increased chance of recovery from disability. In general, the effectiveness of DMTs was most pronounced in subgroups with shorter MS duration, lower EDSS, lower relapse rate and relapsing MS phenotype.

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Microbiome Poster Presentation

P0671 - Exploring the gut microbiome in multiple sclerosis via the international MS Microbiome Study (iMSMS) (ID 1532)

Abstract

Background

The gut microbiota is emerging as a critical regulator of immune responses and appears to play an important role in MS. The International Multiple Sclerosis Microbiome study (iMSMS) is a global collaboration aimed at elucidating the role of commensal gut bacteria in MS by acquiring and analyzing samples from 2000 patients and 2000 household healthy controls.

Objectives

The iMSMS focuses on identifying the microbes, genes and pathways that are involved in MS pathogenesis and on investigating how the microbiome changes response to treatment.

Methods

A total of 576 case and household healthy control pairs were recruited from 7 centers located in the US (West and East coasts), Europe and South America. Stool samples were collected and evaluated by both 16S and shallow whole metagenome shotgun sequencing. Univariate and multivariate linear regression analyses were conducted to understand patterns of variation on gut microbiome.

Results

This is the largest MS microbiome study reported to date. Our results showed a statistically significant difference of beta diversity between MS and healthy controls for the first time in MS. Intriguingly, multiple species of Akkermansia, including the known mucin-degrading bacterium Akkermansia muciniphila, were significantly enriched in untreated MS patients after adjusting for confounding factors, but the difference was not detected in treated MS group versus control. Ruminococcus torques and Eisenbergiella tayi were also among the top significantly enriched bacteria in MS. Inversely, a main butyrate producer, Faecalibacterium prausnitzii, was significantly decreased in the untreated MS group. Functional pathways of L-tryptophan biosynthesis and L-threonine biosynthesis were slightly increased in untreated MS patients, while 5-aminoimidazole ribonucleotide biosynthesis I was increased in the treated group.

Conclusions

Our large household-controlled study allowed us to identify modest but statistically robust MS-associated changes in bacterial composition and functions. It provides the foundation for all future studies of the gut microbiota in MS. The strain-level genomic variation and microbiome-derived molecules need to be further explored for understanding microbial adaptation and pathogenicity.

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Patient-Reported Outcomes and Quality of Life Poster Presentation

P1016 - Designing of a multicenter, non-interventional study to assess subjective disease perception in early-stage relapsing-remitting multiple sclerosis (ID 233)

Presentation Number
P1016
Presentation Topic
Patient-Reported Outcomes and Quality of Life

Abstract

Background

Relapsing-remitting multiple sclerosis (RRMS) has an uncertain prognosis. Patients´ subjective experience living the first few years after the diagnosis may impact their perception of the clinical course, well-being, and decision-making process.

Objectives

To assess the influence of the early-course of the RRMS on patients’ disease perception using a comprehensive standardized battery of patient-reported outcomes.

Methods

A multicenter, non-interventional, cross-sectional study will be conducted with patients diagnosed with RRMS (2017 McDonald criteria) and a disease duration ≤ 3 years (MS-ONSET study).

Demographic characteristics, clinical and imaging outcomes will be collected, including disability (Expanded Disability Status Scale), cognition (Symbol Digit Modalities Test), and magnetic resonance imaging findings. Additional outcomes from the patient´s perspective will be collected, including symptoms severity (SymptoMScreen), mobility (NeuroQol Upper Extremity and 12-item Multiple Sclerosis Walking Scale), health-related quality of life (29-item Multiple Sclerosis Impact Scale), fatigue (5-item Modified Fatigue Impact Scale), mood and anxiety (Hospital Anxiety and Depression Scale), cognition (5-item Perceived Deficit Questionnaire), perception of illness and stigma (Brief Illness Perception Questionnaire and Stigma Scale for Chronic Illness), coping (General Self-Efficacy Scale and Brief Cope), hopelessness (State-Trait Hopelessness Scale), experience of prognosis communication (ad-hoc questionnaire and Miller Behavioral Style Scale), and work-related difficulties and productivity (23-item Multiple Sclerosis Work Difficulties Questionnaire and Valuation of Lost Productivity). Participants will answer questions regarding the management of eight simulated MS case-scenarios based on clinical and radiological disease activity (treatment preferences). They will also complete a survey-experiment based on behavioral economics paradigms to assess risk preferences.

Results

Patient recruitment will begin in June 2020 with a planned total sample of 189 patients and 15 MS units throughout Spain.

Conclusions

The study results are expected to provide meaningful insights into the effect of patients´ perceived seriousness of MS at an early stage. A better understanding of patients´ experience may facilitate shared-decision making and foster the development of specific therapeutic planning in clinical practice.

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Patient-Reported Outcomes and Quality of Life Poster Presentation

P1024 - Economic impact of the Secondary Progressive Multiple Sclerosis in Spain: Interim analysis of the DISCOVER study (ID 1595)

Abstract

Background

Multiple Sclerosis (MS) is a chronic, inflammatory, autoimmune, neurodegenerative disease. Around 19% of treated patients with relapsing-remitting MS progress to Secondary Progressive MS (SPMS) 15 years after disease onset, representing the most severe stage of the disease. MS symptoms lead to a general disability, impacting the quality of life of patients and also being related with an important economic burden on the National Health System, the patients, their caregivers and the whole society.

Objectives

There are limited published data on the economic impact of SPMS. The main objective of the study was to estimate the economic impact of SPMS in Spain.

Methods

DISCOVER (CBAF312AES01) is an observational, non-interventional, cross-sectional, retrospective and multicenter study, including 297 SPMS patients ≥18 years treated and monitored according to routine clinical practice in Spain in 34 public hospitals. All data was collected in one single visit. Primary endpoint: total annual cost per patient, including direct healthcare and non-healthcare costs and indirect costs. Interim results from 99 patients are presented.

Results

62.6% females; mean (SD) age 53.1 (9.3) years; 40.4% with higher education; 86.9% living with a relative. Mean (SD) time since first MS diagnosis was 17.5 (8.9) years and since progression to SPMS 5.2 (4.3) years. At diagnosis, mean (SD) EDSS was 2.0 (1.1), being 5.0 (1.1) at the time of progression and 5.9 (0.8) at the study visit, 47.5% patients reaching EDSS>6. 12.8% of patients presented relapses between 12-24 months before the study. According to EQ-5D-5L, mean (SD) utility (<1) was 0.48 (0.27) for patients with Gd+ lesions and/or relapses 2 years before. According to EQ-5D-5L, mean (SD) utility (<1) for patients with cognitive impairment was 0.45 (0.29) vs 0.51 (0.21) for those without it. Mean (SD) utility for Spanish general population was 0.897 (0.21). EDSS score showed a significative effect (P=0.0074) on the economic burden of the disease, with total costs increasing from 14,546€ (EDSS 4-4.5) to 21,918€ (EDSS 5-5.5) and 26,832€ (EDSS=6). Costs related to patients with EDSS=6 from the societal, patient and healthcare system were 6,441€, 8,450€ and 11,941€, respectively.

Conclusions

Interim results of the DISCOVER study revealed a significant economic impact of MS progression, highlighting the importance of implementing therapeutic strategies specific to the SPMS patient within the early stages of progression.

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Reproductive Aspects and Pregnancy Poster Presentation

P1131 - Pregnancy in a modern day multiple sclerosis cohort: Predictors of postpartum relapse and disability progression (ID 1321)

Abstract

Background

Disease activity has been investigated in pregnant women with RRMS treated with low-efficacy or no therapy. How newer, more efficacious therapies affect relapse and disability progression risk after pregnancy remains understudied.

Objectives

To describe disease activity in a modern pregnancy cohort contrasted with historical cohorts. To determine the predictors of postpartum relapse and the predictors of six-month confirmed disability progression events in a contemporary pregnancy cohort.

Methods

Data were obtained from the MSBase Registry. Term/preterm pregnancies conceived from 2011-2019 (modern cohort) were compared with those conceived between 2005-2010 and pre-2005. Annualised relapse rates (ARR) were calculated for each pregnancy trimester and 12 months either side. Predictors of time-to-relapse postpartum (1st 3 months) and time to 6-month confirmed disability progression event were determined with clustered Cox regression analyses. Breastfeeding duration and time to DMT reinitiation were modelled as time-varying covariates.

Results

We included 1640 pregnancies from 1452 women (modern cohort). Disease-modifying therapy (DMT) used in the year before conception included interferon-beta (n=597), natalizumab (n=219) and fingolimod (n=147). Continuation of DMT up to conception increased over time (31% pre-2005 vs 54% modern cohort). Preconception ARR decreased across epochs (pre-2005: 0·58 [95% CI 0·49-0·70]; 2005-2010: 0·40 [95% CI 0·36-0·45]; modern: 0·29 [95% CI 0·27-0·32]). In all epochs, ARR decreased during pregnancy to reach similar troughs in the 3rd trimester, and rebounded in the 1st 3-months postpartum. Preconception use of high-efficacy DMT predicted early postpartum relapse (hazard ratio (HR) 2.1 [1.4-3.1]); although those on no DMT were also at risk of postpartum relapse, relative to women on low-efficacy DMT (HR 2.7 [1.2-5.9]). Conception EDSS 2, higher preconception and in-pregnancy ARR were also risk factors. DMT reinitiation, particularly of high-efficacy DMT (HR 0.17 [0.07-0.38]), was protective against postpartum relapse. Women who breastfed were less likely to relapse (HR 0.63 [0.42-0.94]). 4.5% of modern pregnancies had confirmed disability progression after delivery. This was predicted by higher pregnancy and postpartum ARR, with postpartum ARR remaining independently predictive in multivariable analysis (HR 1.5 [1.2-2.0]).

Conclusions

The early postpartum period remains a period of vulnerability for disease rebound in women with MS in the modern era. Early DMT reinitiation, particularly with high-efficacy treatment, is protective against postpartum relapse. Confirmed disability progression events after pregnnacy are uncommon in the modern era. Relapse activity is the key driver of these events.

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