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

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

Ultra-high field MRI highlighted the crucial role of cortical injury in multiple sclerosis (MS). Cortical pathology is frequent in MS, and seems to be more pronounced in progressive stages of the disease. One aspect of cortical pathology is represented by focal cortical lesions (CL).

Pioneering studies demonstrated the high frequency of CL in MS, their independence from white matter injury and their clinical relevance, particularly for cognitive impairment. Nevertheless, very few is known about their presence from the onset of the disease, their dynamics of apparition, neither the differential impact of intracortical (IC) and leukocortical (LC) lesions in early MS.

Objectives

The present study aims to assess the prevalence, the topography and the clinical counterpart of cortical lesions in patients included in the first year of MS.

Methods

16 MS patients in the first year of their disease course and 12 matched controls were included. All subjects underwent a 7T brain MRI scan designed to maximize the accuracy of CL detection (sequences: MP2RAGE, FLAIR, FLAWS with 600μm³ isotropic resolution and T2*/QSM with 600μm² in-plane resolution and thickness of 600μm, total acquisition time 58 min). EDSS and MSFC were performed by rated physicians.

Radiological analysis: a cortical lesion was considered in case of signal change with identifiable boundaries compared to adjacent cortex on MP2RAGE, confirmed by at least one other sequence (FLAIR, FLAWS and T2*/QSM), excluding anatomical structure (eg vessels). CL were divided into two groups according to their location: leukocortical when the lesion extended across both white matter (WM) and grey matter (GM) and intracortical when the lesion is exclusively located within the GM. WM lesions were depicted on MP2RAGE and FLAIR sequences with a 3 mm minimal size.

Statistical analysis: patients and lesions descriptive data were presented with means and standard deviation (SD). Spearman correlations were performed between cortical and WM lesions count and clinical evaluations.

Results

Patients' caracteristics: 13 females, 3 males; mean age = 33 yo (SD = 9); mean disease duration = 6 months (SD = 3); mean EDSS = 0.28 (SD=0.51); mean relapse = 1.68 (SD = 1.01).

399 cortical lesions were detected in 14 patients (mean = 11.68, SD = 12.32). Among them 211 LC lesions were seen in 11 patients and 187 IC lesions in 14 patients. Mean number of WM lesions was 27 (SD = 27.45), mean volume was 2.15 mL (SD = 2.75). LC lesions were significantly correlated with WM lesions (ρ=0.91, p<.001). In opposite, IC lesions were not correlated with WM lesions (ρ=0.49, p=0.05) nor LC lesions (ρ=042, p=0.09). No lesions were seen in controls.

No correlations were found between cortical lesions and EDSS nor MSFC.

Conclusions

We evidenced that the prevalence of cortical lesions is very high at the earliest stage of MS and is not correlated with white matter impairment. This study confirms the accuracy of MP2RAGE to depicit these lesions.

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

Ultra-high field MRI highlighted the crucial role of cortical injury in multiple sclerosis (MS). Cortical pathology is frequent in MS, and seems to be more pronounced in progressive stages of the disease. One aspect of cortical pathology is represented by focal cortical lesions (CL).

Pioneering studies demonstrated the high frequency of CL in MS, their independence from white matter injury and their clinical relevance, particularly for cognitive impairment. Nevertheless, very few is known about their presence from the onset of the disease, their dynamics of apparition, neither the differential impact of intracortical (IC) and leukocortical (LC) lesions in early MS.

Objectives

The present study aims to assess the prevalence, the topography and the clinical counterpart of cortical lesions in patients included in the first year of MS.

Methods

16 MS patients in the first year of their disease course and 12 matched controls were included. All subjects underwent a 7T brain MRI scan designed to maximize the accuracy of CL detection (sequences: MP2RAGE, FLAIR, FLAWS with 600μm³ isotropic resolution and T2*/QSM with 600μm² in-plane resolution and thickness of 600μm, total acquisition time 58 min). EDSS and MSFC were performed by rated physicians.

Radiological analysis: a cortical lesion was considered in case of signal change with identifiable boundaries compared to adjacent cortex on MP2RAGE, confirmed by at least one other sequence (FLAIR, FLAWS and T2*/QSM), excluding anatomical structure (eg vessels). CL were divided into two groups according to their location: leukocortical when the lesion extended across both white matter (WM) and grey matter (GM) and intracortical when the lesion is exclusively located within the GM. WM lesions were depicted on MP2RAGE and FLAIR sequences with a 3 mm minimal size.

Statistical analysis: patients and lesions descriptive data were presented with means and standard deviation (SD). Spearman correlations were performed between cortical and WM lesions count and clinical evaluations.

Results

Patients' caracteristics: 13 females, 3 males; mean age = 33 yo (SD = 9); mean disease duration = 6 months (SD = 3); mean EDSS = 0.28 (SD=0.51); mean relapse = 1.68 (SD = 1.01).

399 cortical lesions were detected in 14 patients (mean = 11.68, SD = 12.32). Among them 211 LC lesions were seen in 11 patients and 187 IC lesions in 14 patients. Mean number of WM lesions was 27 (SD = 27.45), mean volume was 2.15 mL (SD = 2.75). LC lesions were significantly correlated with WM lesions (ρ=0.91, p<.001). In opposite, IC lesions were not correlated with WM lesions (ρ=0.49, p=0.05) nor LC lesions (ρ=042, p=0.09). No lesions were seen in controls.

No correlations were found between cortical lesions and EDSS nor MSFC.

Conclusions

We evidenced that the prevalence of cortical lesions is very high at the earliest stage of MS and is not correlated with white matter impairment. This study confirms the accuracy of MP2RAGE to depicit these lesions.