Abstract

There are differences between females and males in terms of susceptibility to multiple sclerosis (MS), MS activity and MS prognosis, with a certain paradox, females being more susceptible to develop the disease, but having a better long term prognosis. These differences could be related to variations in sex hormones levels. The most striking evidence comes from pregnancy data, where the increase in sex hormones impregnation is accompanied by a dramatic decrease in the risk of relapses, whereas the post-partum decrease in hormones leads to a rebound of MS activity. In the presentation, we will go through the different states in women’s life, considering natural and therapeutic hormonal changes and their relation to MS susceptibility, activity and prognosis, from a clinical and epidemiological standpoint.

Background

Risk factors associated with the severity of COVID-19 in patients with multiple sclerosis (MS) begin to be identified from several cohort studies. Disease modifying therapies (DMTs) may modify the risk of developing a severe COVID-19 infection, beside identified risk factors such as age and comorbidities.

Objectives

The objective was to describe the clinical characteristics and outcomes in patients with COVID-19 and to identify the factors associated with COVID-19 severity.

Methods

This multicenter, retrospective, observational cohort study (COVISEP registry, NCT04355611) included patients with MS presenting with a confirmed or highly suspected diagnosis of COVID-19 between March 1, 2020 and July 14, 2020. The main outcome was COVID-19 severity assessed on a 7-point ordinal scale (ranging from 1: not hospitalized, no limitations on activities, to 7: death; cutoff at 3: hospitalized, not requiring supplemental oxygen). We collected demographics, neurological history, Expanded Disability Severity Score (EDSS), comorbidities, COVID-19 characteristics and outcome. Univariate and multivariate logistic regression models were used to estimate the influence of collected variables on COVID-19 outcome.

Results

A total of 405 patients (mean age: 44.7 years, female/male: 293/112, mean disease duration: 13.4 years) were analyzed. Seventy-eight patients (19.3%) had a COVID-19 severity score ≥ 3, and 12 patients (3.0%) died from COVID-19. Median EDSS was 2.0 (range: 0-9.5), 326 patients (80.5%) were on DMT. There was a higher proportion of patients with COVID-19 severity score ≥ 3 among patients with no DMT relative to patients on DMTs (39.2% versus 14.4%, p<0.001). Multivariate logistic regression models determined that age (OR for 10 years: 1.8, 95% CI: 1.4-2.4), EDSS (OR for EDSS ≥ 6: 4.5, 95% CI: 2.0-10.0) were independent risk factors for COVID-19 severity score ≥ 3 (hospitalization or higher severity) while immunomodulatory treatment (interferon or glatiramer acetate) was associated with lower risk of COVID-19 severity score ≥ 3 (OR: 0.2, 95% CI: 0.05-0.8). EDSS was associated with the highest variability of COVID-19 severe outcome (R²= 0.18), followed by age (R²= 0.06) and immunomodulatory treatment (R²= 0.02).

Conclusions

EDSS and age were independent risk factors of severe COVID-19, while exposure to immunomodulatory DMTs (interferon and glatiramer acetate) were independently associated with lower COVID-19 severity. We did not find an association between other DMTs exposure (including immunosuppressive therapies) and COVID-19 severity. The identification of these risk factors should provide the rationale for an individual strategy regarding clinical management of MS patients during the COVID-19 pandemic.

Background

To predict the clinical course of myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated disease (MOGAD) is essential to guide treatment recommendations.

Objectives

We aimed to 1) compare clinical features and disease course, and 2) to evaluate the association of MOG-Ab dynamics and relapses, between children and adults with MOGAD.

Methods

Retrospective study evaluating clinical features of 98 children and 266 adults with MOGAD, between January 2014 and September 2019. To analyse relapses over the whole disease course, a Cox regression analysis for recurrent time-to-event data was performed, introducing treatment as time-dependent covariate. To evaluate dynamics, delta mean fluorescence intensity ratio signal (ΔMFIratio) of MOG-Ab was measured in patients with a minimum time elapsed between two samples of 4 months.

Results

Median age at onset of symptoms was 10.9 (interquartile range 5.4-14.3) years in children and 36.2 (27.7-47.6) in adults. Isolated optic neuritis was the most frequent clinical presentation both in children (40.8%) and adults (55.9%), p=0.013, and acute disseminated encephalomyelitis syndrome was more frequent in children (36.7% vs. 5.6%; p<0.001). Compared to adults, children displayed a better recovery (EDSS ≥3.0 at last follow-up reached only by 10 of 97 [10.3%] vs. 66/247 [26.7%], p<0.001).

In the multivariate analysis, adults were at higher risk of relapse than children (Hazard ratio 1.41, 95%Confidence interval [CI] 1.12-1.78; p=0.003). Among the 124 participants evaluated for MOG-Ab dynamics, 36.3% became seronegative, 60.5% decrease and 3.2% increase the ΔMFIratio. At two years, 64.2% (95%CI 40.9-86.5) of non-relapsing children became MOG-Ab negative compared to 14.1% (95%CI 4.7-38.3) of relapsing ones, log-rank p<0.001, with no differences observed between non-relapsing and relapsing adults, log-rank p=0.280.

Conclusions

MOGAD differs in its clinical presentation at onset, showing a progressive shift in the clinical features across age-groups. Compared to children, adults have a higher risk of relapses and a worse functional recovery. Finally, children with monophasic disease became MOG-Ab negative earlier than relapsing ones, but not in adults. Considering these differences, management and treatment guidelines should be considered independently in children and adults.

Abstract

There are differences between females and males in terms of susceptibility to multiple sclerosis (MS), MS activity and MS prognosis, with a certain paradox, females being more susceptible to develop the disease, but having a better long term prognosis. These differences could be related to variations in sex hormones levels. The most striking evidence comes from pregnancy data, where the increase in sex hormones impregnation is accompanied by a dramatic decrease in the risk of relapses, whereas the post-partum decrease in hormones leads to a rebound of MS activity. In the presentation, we will go through the different states in women’s life, considering natural and therapeutic hormonal changes and their relation to MS susceptibility, activity and prognosis, from a clinical and epidemiological standpoint.

Abstract

There are differences between females and males in terms of susceptibility to multiple sclerosis (MS), MS activity and MS prognosis, with a certain paradox, females being more susceptible to develop the disease, but having a better long term prognosis. These differences could be related to variations in sex hormones levels. The most striking evidence comes from pregnancy data, where the increase in sex hormones impregnation is accompanied by a dramatic decrease in the risk of relapses, whereas the post-partum decrease in hormones leads to a rebound of MS activity. In the presentation, we will go through the different states in women’s life, considering natural and therapeutic hormonal changes and their relation to MS susceptibility, activity and prognosis, from a clinical and epidemiological standpoint.

Background

At any time in multiple sclerosis (MS) management, a disease-modifying therapy (DMT) stop, restart or change can occur. In PRO-MSACTIVE (NCT03589105), an open-label, single-arm, phase IV study designed to evaluate the efficacy, safety and impact of ocrelizumab on patient reported outcomes in patients with active relapsing MS (RMS), every patient’s treatment history was gathered.

Objectives

To describe the therapeutic management of French patients with active RMS (relapsing-remitting [RRMS] and secondary progressive [SPMS]), as reported at baseline, prior to the first ocrelizumab infusion (IV OCR).

Methods

PRO-MSACTIVE is being conducted in France (46 active centers) in patients with active RMS, ≥18 years old, naïve or pretreated with DMT. Washout periods between the last DMT taken by the patient and baseline IV OCR were pre-specified. For each patient, all previous DMTs were collected during the screening period, ≤4 weeks prior to baseline.

Results

Treatment history was documented for the 422 enrolled patients: 376 RRMS and 46 SPMS. Most (74.9%) had at least one previous DMT prior to the first IV OCR: 73.9% for RRMS and 82.6% for SPMS patients. The longest therapeutic sequence includes 8 DMTs prior to the first IV OCR. The most frequent previous DMTs were β interferons and assimilated products (IFN-AP) (51.4% all patients, 49.2% RRMS, 69.6% SPMS); selective oral immunosuppressants (30.8% all patients, 30.6% RRMS, 32.6% SPMS; mainly fingolimod); and teriflunomide (24.2% all patients, 24.5% RRMS, 21.7% SPMS). IFN-AP ranked first among the older DMTs (46.5% all patients, 45.0% RRMS, 58.7% SPMS). Mean time (standard deviation, SD) from the oldest DMT to the first IV OCR was 6.55 yrs (5.44) for RRMS patients, and 14.20 yrs (8.46) for SPMS patients. The most recent DMTs prior to IV OCR were fingolimod (22.8% all patients, 23.7% RRMS, 15.2% SPMS); dimethyl fumarate (14.7% all patients, 15.7% RRMS, 6.5% SPMS); teriflunomide (14.5% all patients, 14.6% RRMS, 13.0% SPMS); IFN-AP (14.0% all patients, 14.1% RRMS, 13.0% SPMS); and natalizumab (4.3% all patients, 4.5% RRMS, 2.2% SPMS). Mean time (SD) from the most recent DMT to the first IV OCR was 2.65 yrs (2.12) for RRMS patients and 3.01 yrs (2.85) for SPMS patients.

Conclusions

Treatment history with DMTs prior to the first IV OCR is well characterized in the PRO-MSACTIVE study. These data permit a better understanding of the therapeutic strategies in RMS patients in current medical practice.

Background

Pregnancy management in patients with relapsing-remitting multiple sclerosis (MS) treated by Natalizumab (NTZ) is challenging because of the risk of disease reactivation after treatment discontinuation.

Objectives

To compare clinical disease activity (annual relapse rate) during and after pregnancy among three therapeutic approaches: continuation of NTZ all along the pregnancy and the postpartum, discontinuation of NTZ in the second trimester and discontinuation of NTZ before pregnancy.

Methods

Data were collected from the French MS registry OFSEP (Observatoire Français de la Sclérose en Plaques). We included patients with relapsing-remitting MS who started a pregnancy between 6/2013 and 9/2018 while taking NTZ, or within six months after its suspension. 3 groups were compared : continuation of NTZ throughout pregnancy and postpartum (Group 1), 3 to 6 months of exposure to NTZ during pregnancy (Group 2) and suspension prior to pregnancy (Group 3). Annual relapse rate (ARR) during 2 years (9 months before and 15 months after preganncy onset) was the primaty outcome and effect on EDSS and MRI were secondary end-points.

The main analysis was performed using a negative binomial regression with the follow-up duration as the offset term. Univariate and multivariate anlyses after adjustment for baseline variables (age, EDSS, ARR in the year before starting NTZ, first-line patient on NTZ vs. second-line patient).

Results

117 patients from 27 centers* were included. Baseline mean age was 31,5 y, median EDSS was 2.0 and mean duration of disease was 7,89 y. The mean ARR were respectively 0.078 +/- 0.24 in Group 1, 0.308 +/- 0.43 in Group 2 and 0.456 +/- 0.63 in Group 3 during the observation period and was significantly higher in Groups 2 and 3 as compared with ARR in Group 1 (p=0,007). The risk of relapses was 4 times higher in Group 2 versus Group 1 (p=0,014) and 6 times higher in Group 3 versus Group 1 (p=0,001).

Multivariate analyses did not show any effect of the adjustment variables.

Evaluation of safety outcomes on the mother and the fetus is in progress.

* Investigators: AR, JCO, CD, PB (Bordeaux), SD, BA, AR, AM, CB, JP (Marseille), MD, S Pitton (Nancy), JD (Strasbourg), TM (Dijon), JC, D Biotti (Toulouse), OC, M Vaillant (Grenoble),E Berger (Besançon), D Laplaud (Nantes), G Defer (Caen), I Patry (Corbeil-Essonnes), P Vermersch (Lille), P Labauge (Montpellier), O Bourre (Rouen), B Stankoff (Paris-Saint-Antoine), A Créange (Créteil), P Cabre (Fort-de-France), E Thouvenot (Nîmes), T De Broucker (Saint-Denis), C Papeix (Paris-Salpêtrière), P Clavelou (Clermont-Ferrand), O Gout (Paris-F.Rothschild), A Montcuquet (Limoges), C Lebrun (Nice), O Heinzlef (Poissy) N Maubeuge (Poitiers).

Conclusions

Continuation of Natalizumab during all three trimesters of pregnancy is associated with a lower risk of relapses as compared with discontinuation before the pregnancy or even during the second trimester.

Safety data is being collected.

Background

There is little data on the description of Secondary Progressive Multiple Sclerosis (SPMS) in France, notably because there is a lack of therapeutic options to slow down the disease progression during that phase.

Objectives

Describe and understand Secondary Progressive Multiple Sclerosis (SPMS) clinical course and therapeutic management in France.

Methods

A retrospective multicentric observational study (ODYSSEP study) involving clinical longitudinal data was performed from the French prospective national cohort of MS patients (OFSEP). Inclusion criteria were diagnosis of SPMS and at least one clinical visit between 2013, January 1st and 2017, June15th. Sensitivity analysis, was also performed to include undiagnosed SPMS patients in OFSEP database using an automatized algorithm detecting patients with an increase in EDSS score without any activity (relapses and/or evidence of new MRI activity) between two clinical evaluations.

Results

3140 SPMS patients were included in the main analysis, and 454 additional patients were identified through the sensitivity analysis. Median age at onset of progression was 47 years, and 68% of the patients were women. Almost half of patients (48%) had at least one relapse during the follow-up; whereas only 10% had one during the last year of follow-up. Median EDSS at onset of progression was 4.5. During the follow-up of 9 years in mean, an increase of 1.6 points in EDSS score was observed. Treatments were described among the 908 patients with progression onset after 2013 specifically. At the time of SPMS diagnosis, 35.4% of patients were untreated, 30.6% and 26.3% were treated by first- and second-line disease modifying therapy (DMT)(mainly IFN: 13.4%), 6.4% by off-label treatments and 1.3% by biotin. During the SP phase, 63.6% of patients received at least one DMT; 30.6% were treated with first-line and 26.3% with second-line DMT. At the last clinical visit, 56.2% of patients were still treated, mainly by off-label treatments (26.5%); first-line and second-line DMT were less used (14.9% and 14.4%, respectively). Biotin was also frequently used (16.1%), either as the main treatment (10.6%) or associated with a DMT (5.5%).

Conclusions

These real world results from the French MS cohort indicate that most of SPMS patients are either untreated or taking off-label drugs. It reflects the current lack of satisfactory therapeutic options during the secondary progressive phase of MS and underlines the urgent need for new efficacious drugs specifically approved for SPMS.

Background

In secondary progressive multiple sclerosis (SPMS), reduction in the rates of disability accrual after starting disease modifying therapy (DMT) has largely been limited to patients with ongoing inflammatory activity. A delayed treatment effect, termed therapeutic lag, may obscure therapeutic benefits in SPMS.

Objectives

To compare the effect of high and low efficacy DMT on disability outcomes in patients with recently active and inactive SPMS after accounting for therapeutic lag.

Methods

Using data from MSBase, a multinational MS registry, and OFSEP, the French MS registry, we identified patients with SPMS as per a previously validated objective definition. We identified patients treated with high- (natalizumab, alemtuzumab, mitoxantrone, ocrelizumab, rituximab, cladribine, fingolimod) or low-efficacy (interferons, glatiramer acetate, teriflunomide) DMT after SPMS onset. Based on our previous work, an individualised estimate of duration of therapeutic lag was calculated for each patient. Only events that occurred after the estimated therapeutic lag period were included in the analysis. Propensity score matching was used to select groups with comparable baseline characteristics. Disability and relapse outcomes were compared in paired, pairwise-censored analyses adjusted for visit density.

Results

Of 7359 patients with SPMS, 1000 patients fulfilled the criteria for study inclusion (510 active SPMS, 490 inactive SPMS). For the relapse outcomes, patients with active SPMS treated with high-efficacy DMTs experienced lower probabilities of relapses than low-efficacy DMTs (hazard ratio [HR] 0.7 [95%CI 0.5-0.9], p=0.006). Patients with inactive SPMS had similar probabilities of relapses in the high and low efficacy DMT groups (0.8 [0.6-1.2], p=0.39). No difference in the risk of 6-month sustained disability accumulation, or proportion of patients reaching EDSS>=7, was observed between groups when accounting for therapeutic lag.

Conclusions

The risk of disability accumulation in SPMS seems to be comparable in patients treated with high- and low- efficacy DMT. High efficacy DMT is superior to low efficacy therapy in reducing relapse activity in patients with active SPMS, but not those with inactive SPMS. Pre-treatment inflammatory activity, clinical or radiological, is a treatable target in SPMS which may benefit from higher-efficacy anti-inflammatory therapies.

Background

Assessment of the impact of fingolimod exposure on pregnancy outcomes is essential for the management of multiple sclerosis in pregnant women or those planning to conceive.

Objectives

To report the prevalence of major congenital malformations (MCMs) in infants following fingolimod exposure before (up to 8 weeks before last menstrual period) or during pregnancy.

Methods

Cumulative pregnancy outcome data are reported from prospective cases in the Novartis Safety database (NSDB) and Multinational Gilenya^®Pregnancy Exposure Registry (GPR, which comprises a subset of NSDB cases also). For data in the NSDB and GPR, prospective cases were those for which pregnancy outcome was unknown and condition of the fetus was not assessed through prenatal testing at the time of enrolment. For the NSDB, if prenatal testing was not performed and results were either normal/not known, cases were also considered prospective. The prevalence (95% confidence interval [CI]) of MCMs in live births was estimated.

Results

As of 28^th February 2020, 1762 prospective cases of maternal fingolimod exposure during pregnancy were reported in the NSDB and 177 in the GPR. Of all pregnancies with a known outcome, live births were: 754 (70.9%) in NSDB and 130 (85.0%) in GPR. Estimated prevalence of MCMs among live births was 3.19% (95% CI: 2.05; 4.71) in the NSDB and 4.6% (95% CI: 1.7; 9.8) in the GPR. As per recent meta-analysis, MCM prevalence in untreated MS is estimated to be 4.2% (95% CI: 2.7; 6.1), which is in line with that reported in this study. As per European Registration of Congenital Anomalies and Twins (EUROCAT), MCM prevalence in general population is 2.6% (95% CI: 2.6; 2.6). No clear discernible pattern of specific malformation was observed in the GPR. In the NSDB, the estimate of the proportion of live births with major cardiovascular anomalies (1.33% [95% CI: 0.64; 2.43]) was larger than, but not significantly different from the corresponding EUROCAT prevalence estimate (0.69%). This may be attributable to the difference in data collection and processing methodologies between EUROCAT and the NSDB.

Conclusions

The overall prevalence estimates of MCMs among live births in the NSDB and GPR are similar to that from the untreated MS population. Although both prevalence estimates are higher than the EUROCAT general population prevalence, it is within 95% CIs for both databases. The wide 95% CI in the GPR prevents firm conclusions regarding increased risk of MCMs in fingolimod exposed patients.

Background

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for the treatment of relapsing and primary progressive multiple sclerosis (MS). As many MS patients are women of reproductive age, pregnancy outcomes in OCR-exposed patients are of relevance.

Objectives

To report an update on pregnancy outcomes in women with MS receiving OCR in clinical trials and post-marketing.

Methods

Analysis includes pregnancies in women receiving OCR in clinical trials/post-marketing (global safety database). Women of childbearing potential should use contraception while on treatment and for 6 or 12 months after the last OCR infusion, depending on local regulations. Based on the average terminal half-life of 26 days and the lack of relevant placental transfer in the 1^st trimester, a fetus was considered to have fetal OCR exposure if the last infusion occurred within 3 months of conception, during pregnancy, or if the date was unknown.

Results

As of March 27, 2020, 726 total pregnancies exposed to OCR in women with MS (n=608) or unknown indication (n=118) were reported. Of the 608 MS pregnancies, 234 were considered to have fetal OCR exposure, 102 were not, and 272 had unknown exposure. Preliminary outcomes of total MS pregnancies (n/%) were: 156/64.2% live births, 37/15.2% elective/therapeutic abortions, 42/17.3% spontaneous abortions, 3/1.2% stillbirths, 5/2.1% ectopic pregnancies; 134 pregnancies were ongoing, 80 lost to follow-up (FU) and 151 had unknown/not reported (NR) outcomes. Of the 156 total live births, 6 congenital malformations were reported. Preliminary outcomes of MS pregnancies with fetal OCR exposure (n/%) were: 62/59.6% live births, 24/23.1% elective/therapeutic abortions, 15/14.4% spontaneous abortions, 2/1.9% stillbirths, 1/1.0% ectopic pregnancies; 55 pregnancies were ongoing, 37 lost to FU and 38 had unknown/NR outcomes. Infant health questionnaires were received from 13 live births with up to 1-year FU and will continue to be collected, including data on vaccinations and infections: 9 infants had no infections and 1 had a resolved infection.

Conclusions

Cases reviewed to date do not suggest an increased risk of adverse pregnancy outcomes (including spontaneous abortions or malformations) with OCR use, whether or not fetal exposure occurred or was unknown. The updated outcomes remain in line with prior reports and within the expected epidemiologic range. Data continue to be collected and assessed as per post-authorization commitments.