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 1^st 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 (3^rd 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.

Background

The concept of no evidence of disease activity-3 (absence of brain MRI and clinical disease activity; NEDA-3) in multiple sclerosis (MS) reflects disease activity with limited sensitivity. The added value of neurofilament light chain levels in serum (sNfL) to NEDA-3 has not yet been investigated.

Objectives

To assess whether sNfL allows to identify among patients with and without NEDA-3 status those at higher risk of future disease activity and accelerated brain volume loss.

Methods

We analyzed 369 samples from 155 early relapsing-remitting MS patients (SET study). sNfL levels and brain MRI scans were evaluated annually. The comparison of subgroups defined by high or low sNfL (>90^th or <90^th percentile of healthy controls of the same age) and NEDA-3 status was performed by generalized estimating equation models. Changes in global and regional brain volumes were calculated on three-dimensional T1-weighted scans.

Results

Patients with disease activity (EDA-3) in the preceding year and high sNfL, compared to those with low sNfL, had: a) higher odds of EDA-3 in the following year (87% versus 58%; OR 4.39, 95%-CI:2.18, 8.94; p<0.001), b) greater whole brain volume loss during the following year (0.39%, 95%-CI:-0.63, -0.16; p<0.001) and c) greater whole brain volume loss (0.61%, 95%-CI:-0.66, -0.17; p<0.001) during the preceding year. Accordingly, NEDA-3 patients with high sNfL showed a trend for a return of disease activity (EDA-3) in the following year compared with those with low sNfL (57% versus 31%).

Conclusions

High sNfL levels are associated with increased future risk of disease activity and accelerated brain volume loss. Adding of sNfL improves the prognostic value of the NEDA-3 concept.

Background

Over 6 years in the CARE-MS core and extension trials (NCT00530348; NCT00548405; NCT00930553), alemtuzumab improved outcomes in RRMS patients, but many experienced thyroid adverse events (AEs).

Objectives

To characterize thyroid AEs over 6 years in alemtuzumab-treated patients from the CARE-MS core and extension trials.

Methods

Patients received 2 alemtuzumab courses, with as-needed additional alemtuzumab ≥12 months after the most recent course. An expert panel of 3 independent endocrinologists reviewed all reported cases of thyroid-related laboratory abnormalities and AEs to assess diagnosis, start date, and outcome through a consensus approach. Cases for which consensus was not reached, or those that were preexisting or occurred after Y6 were excluded.

Results

Over 6 years, 378/811 (47%) alemtuzumab-treated patients had a thyroid AE or laboratory abnormality (342 [42%] with thyroid AE; 44 serious AEs). After panel review, 292 cases had a consensus diagnosis as a thyroid AE, no consensus diagnosis could be reached in 60 cases, 2 cases were deemed pre-existing, and 24 occurred after Y6. Cases with a consensus diagnosis were adjudicated to Graves’ disease (40%), Hashimoto’s disease (17%), transient thyroiditis (8%), Graves’ disease switching to hypothyroidism (6%), Hashimoto’s disease switching to hyperthyroidism (3%), or uncertain (27%). Oral thyroid medications were given to 245/292 (84%) patients, primarily levothyroxine/levothyroxine sodium (n=187; 64%) or thiamazole (n=126; 43%); 32/292 (11%) patients underwent thyroidectomy and 26/292 (9%) underwent radioiodine therapy. Within 2 years of the last alemtuzumab course, 83% of thyroid AEs appeared (>97% were detected within 4 years). Patients with vs without thyroid AEs received similar numbers of alemtuzumab courses (2 courses: 62% vs 60% of patients; 3 courses: 24% in each group). From baseline to Y6, MS disease outcomes were similar in patients with vs without thyroid AEs (annualized relapse rate: 0.20 vs 0.21; mean EDSS score change: −0.04 vs +0.08; proportion with stable/improved EDSS scores: 81% vs 80%; proportions MRI disease activity-free: 60%-78% per year vs 60%-76% per year; and median cumulative brain volume loss: −1.11% vs −1.27%). Outcomes as of last follow-up were recovered (53%), ongoing (46%), and unknown (0.3%).

Conclusions

Graves’ disease was the most common thyroid AE. Most thyroid AEs were treated with oral medications. No differences in 6-year MS disease outcomes were seen when comparing patients with or without thyroid AEs.

STUDY SUPPORT: Sanofi and Bayer Healthcare Pharmaceuticals.

Background

Serum neurofilament light chain (sNfL) levels reflect only neuro-axonal injury that took place within 3-6 months prior to the date of sampling. Therefore, the frequency of assessment of sNfL levels for monitoring of disease activity warrants further investigation.

Objectives

To determine differences in accuracy of sNfL levels to detect radiological disease activity during the preceding 6 versus 12 months of follow-up.

Methods

This observational study included 148 patients with early relapsing-remitting multiple sclerosis (MS) from the SET cohort. Based on brain MRI performed at 0, 6 and 12 months, we assessed the ability of categorized sNfL measured at 12 months to reflect the presence of combined unique active lesions, defined as new/enlarging lesion compared with MRI performed in the previous 6 versus 12 months or contrast-enhancing lesion (e.g., active lesions).

Results

Together, 91% (95% CI=85-98%) of patients with ≥1 active lesion during the last 6 months and 84% (95% CI=77-92%) of patients with ≥1 active lesion during the last 12 months had sNfL≥30^th percentile. Among the patients with sNfL<30^th percentile, 14 (33.3%) developed ≥1 active lesion during the last 12 months, but only 6 (14.3%) developed ≥1 active lesion during the last 6 months. Among patients with sNfL<30^th percentile, 6 (14.3%) developed ≥2 active lesions during the last 12 months, but only 2 (4.8%) developed ≥2 active lesions during the last 6 months.

Conclusions

Low levels of sNfL better identified MS patients with the absence of recent radiological disease activity during the previous 6 than the previous 12 months. In the future, assessment of sNfL at least every 6 months may substitute the need for annual brain MRI monitoring to exclude brain lesion activity in clinically stable patients with low sNfL levels.

Background

OPTIMUM was a multicenter, double-blind, active-comparator phase 3 superiority trial that assessed efficacy, safety, and tolerability of ponesimod 20 mg (PON) vs teriflunomide 14 mg (TER) in patients with relapsing multiple sclerosis (RMS). The primary endpoint of annualized relapse rate was met demonstrating PON’s superiority vs TER.

Objectives

To assess treatment effect on disability progression using time to worsening of timed 25-foot walk (T25FW), 9-Hole Peg Test (9HPT), Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test [PASAT-3] , Expanded Disability Status Scale (EDSS) and composites of these endpoints.

Methods

OPTIMUM enrolled patients with RMS (EDSS:0-5.5), randomized (1:1) to daily PON or TER for 108 weeks. Change in MS functional composite (MSFC) Z-score (mean of T25FW, 9HPT, PASAT-3 Z-scores), and SDMT from baseline to Week 108 was assessed using Mixed-Effect Model Repeated Measures. Analyses of time to first confirmed (12-week) disability event were conducted post-hoc; disability was defined as 4-point worsening in SDMT, 20% worsening in T25FW or 9HPT, in addition to EDSS (as defined for the secondary endpoint).

Results

Of 1133 patients (PON=567, TER=566), 86.9% completed study. Changes from baseline in overall MSFC Z‑score: 0.02 PON vs −0.039 TER (mean difference, 0.059; p=0.047); for the 3 individual components of MSFC Z-score, mean differences (p-values) were: T25FW, 0.20 sec (p=0.37); 9HPT, –0.93 sec (p<0.0001); PASAT-3, 0.55 number correct (p=0.16). The PON vs TER worsening events up to EOS were, respectively: confirmed 20% worsening in T25FW, 9.2% vs 13.1% (hazard ratio [HR]:0.70; p=0.045); 4-point worsening in SDMT, 22.1% vs 26.4% (HR:0.82; p=0.12)], composite EDSS/SDMT, 26.3% vs 32.7% (HR:0.80; p=0.045)]; composite EDSS/9HPT/T25FW, 18.2% vs 24.0% (HR:0.76; p=0.035); numerical differences in favour of PON in time to confirmed worsening in 9HPT and SDMT assessed individually were not statistically significant.

Conclusions

Measures of worsening of impairment and disability in this exploratory analysis indicated benefits for PON vs TER. Composite endpoints provide more power to statistical assessments owing to greater number of events analyzed, making them particularly useful in RMS trials.

Background

Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in the US and EU for the treatment of relapsing forms of multiple sclerosis (RMS).

Objectives

To characterize the long-term safety and efficacy of ozanimod in participants with RMS in an ongoing open-label extension (OLE) trial.

Methods

Participants with RMS who completed a phase 1, 2, or 3 ozanimod clinical trial were eligible to enroll in DAYBREAK (NCT02576717), where they received ozanimod 0.92 mg/d (equivalent to ozanimod HCl 1 mg). The primary objective was to evaluate safety in the overall population; treatment-emergent adverse events (TEAE) were monitored. Efficacy was evaluated with annualized relapse rate (ARR), calculated via negative binomial regression and pooled for all parent-trial treatment groups. Number of new/enlarging T2 and gadolinium-enhancing (GdE) MRI brain lesions were reported for the subset of participants who entered the OLE from an active-controlled phase 3 trial.

Results

In total, 2639 participants completed the parent trials; this interim analysis (data cut 20 December 2019) included 2494 participants with mean (range) ozanimod exposure of 35.4 (0.03–50.2) months in the OLE. Adjusted ARR in the OLE was 0.112 (95% confidence interval, 0.093‒0.135). At months 24 and 36, 79% and 75% of participants, respectively, were relapse free in the OLE. Three- and 6-month confirmed disability progression was observed in 10.8% and 8.6% of participants in the OLE, respectively. Mean number of new/enlarging T2 lesions per scan at 24 months was similar, regardless of parent-trial treatment group (range, 1.57–1.90), as were mean number of GdE lesions at month 24 (range, 0.2 ‒0.4). In the OLE, 2039 participants (81.8%) had any TEAE, 236 (9.5%) had a serious TEAE (SAE), and 56 (2.2%) discontinued due to a TEAE. Similar rates of TEAEs and SAEs occurred when assessed by parent-trial treatment group. The most common TEAEs were nasopharyngitis (17.9%), headache (14%), upper respiratory tract infection (9.9%), and lymphopenia (9.6%). TEAEs were generally similar to parent trial observations. There were no serious opportunistic infections. Exposure-adjusted incidence rates of TEAEs and SAEs have decreased over time.

Conclusions

In DAYBREAK, ozanimod was associated with low ARR and low new/enlarging T2 and GdE lesion counts over time. Most participants were relapse free and did not experience disability progression. Ozanimod was generally well tolerated and no new safety concerns emerged with long-term use.

Background

Although conventional MRI acquisitions are of essence in the monitoring of MS, they show low specificity towards the microstructural nature of tissue alterations and exhibit rather low correlations with clinical metrics (“clinico-radiological paradox”). Conversely, recent advances in brain relaxometry allow characterizing microstructural alterations on a single-subject basis; the question yet remains whether such quantitative measurements can help bridging the gap between radiological and clinical findings.

Objectives

This study investigates whether automatically assessed alterations of T₁ relaxation times in brain lesions and normal-appearing white matter (NAWM) improve clinico–radiological correlations in early MS with respect to conventional measures.

Methods

102 healthy controls (65% female, [21-59] y/o) and 50 early-MS patients (76% female, [19-52] y/o) underwent MRI at 3T (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany). The employed 3D protocol comprised MPRAGE, FLAIR (both used for lesion segmentation as in [Fartaria et al., 2017, MICCAI]), and MP2RAGE for T₁ mapping.

After the healthy controls’ data were spatially normalized into a study-specific template, reference T₁ values in healthy tissues were established by linear, voxel-wise modelling of the T₁ inter-subject variability [Piredda et al., MRM, 2020]. In the MS cohort, T₁ deviations from the established references were calculated as z-score maps.

Correlations between the EDSS and conventional measures, i.e. lesion volume and count, were compared against correlations with z-score-derived metrics in lesions and NAWM, namely the volume of voxels exceeding a given z-score threshold.

Results

Correlations between EDSS and lesion volume and count were found to be 0.23 and 0.18, respectively. Higher correlations were found between EDSS and the volume of voxels exceeding an absolute z-score threshold of 2, both in lesions and NAWM, with ρ=0.3 and ρ=0.33, respectively. Correlation further improved when considering only negative z-scores, ρ=0.36 for lesions and ρ=0.39 for NAWM. The highest correlation was found when considering absolute z-scores in the occipital lobe NAWM, ρ=0.47.

Conclusions

Microstructural alterations identified as T₁ z-scores were found to improve clinico–radiological correlation in comparison to conventional measures (lesion volume and count). Of notice, negative z-scores (i.e. abnormal T₁ shortening), which may be due to an increase in iron content, appear to be a potential predictor for the clinical state of an early MS patient.

Background

To date, no studies have explored the relationship between brain atrophy and MS disability using differing MRI protocols and scanners at multiple sites.

Objectives

To assess the association between brain atrophy and MS disability, as measured by EDSS and 6-month confirmed disability progression (CDP).

Methods

In this retrospective study at 4 MS centres, a total of 1300 patients had brain MRI imaging assessed by icobrain. Relapse-onset MS patients were included if they had two clinical MRIs 12 (±3) months apart and ≥2 EDSS scores post MRI-2, the first ≤3 months from MRI-2, with ≥6 months between first and last EDSS. Volumetric data were analysed if the alignment similarity between two images was as good as that of same-scanner scan-rescan images (normalised mutual information ≥0.2). The percentage brain volume change (PBVC), percentage grey matter change (PGMC), FLAIR lesion volume change, whole brain volume, grey matter volume, FLAIR lesion volume and T1 hypointense lesion volume at MRI-2 were calculated. Ordinal mixed effect models were used to determine the association between these volumetric MRI measures and all EDSS scores post MRI-2. Cox proportional hazards models were used for the 6-month CDP outcome, using a subset of patients with ≥3 EDSS. Models were adjusted for proportion of time spent on disease-modifying therapy during MRIs ± whole brain/grey matter volume at baseline MRI.

Results

Of the 260 relapse-onset MS patients included, 204 (78%) MRI pairs were performed in the same scanner and 56 (22%) pairs were from different scanners. During the follow-up period (median 3.8 years, range 1.3-8.9), 29 of 244 (12%) patients experienced 6-month CDP. There was no evidence for association between annualised PBVC or PGMC and CDP or EDSS (p>0.05). Cross-sectional whole brain and grey matter volume (at MRI-2) tended to associate with CDP (HR 0.99, 95% CI 0.98-1.00, p=0.06). Every 1ml of whole brain or grey matter volume lost represented a 1% higher chance of reaching 6-month CDP. Only whole brain volume (at MRI-2) was associated with EDSS score (β -0.03, SE 0.01, p<0.001) and the slope of EDSS change over time (β -0.001, SE 0.0003, p=0.02). On average, every 33ml reduction of brain volume was associated with a 1 step increase in EDSS.

Conclusions

In this real-world clinical setting where a fifth of the brain atrophy analysis were performed on different scanners, we found no association between individual brain atrophy and MS disability. However, there was an association between cross-sectional whole brain volume with EDSS and slope of EDSS change.

Background

The dynamic of lesion activity and brain volume changes during the post-partum period in women with multiple sclerosis (MS) is not well understood.

Objectives

To describe the evolution of clinical and radiological disease activity, including brain volume loss during the pregnancy and post-partum period.

Methods

In this observational study of 62 women with relapsing-remitting MS, all 221 brain MRI scans were performed on the same 1.5-Tesla scanner. T2 lesion and brain volumes were analyzed by ScanView. MRI and clinical visits were scheduled at: late pre-pregnancy period: <24 and >6 months before pregnancy (56-measures); early pre-pregnancy period: <6 months before pregnancy (62-measures); early post-partum period: <3 months after delivery (62-measures); and late post-partum period: >12 and <24 months after delivery (41-measures). Differences in disease activity among time points were analyzed using the Wilcoxon signed-rank test.

Results

Eighteen (29.0%) women had a relapse during the year preceding pregnancy-onset, 9 (14.5%) women had a relapse during the pregnancy and 20 (32.3%) women had a relapse during the year following delivery. Disability status, as assessed by the expanded disability status scale (EDSS) remained unchanged during the follow-up. Women in early post-partum period (post) had higher T2 lesion volume (median: 0.94 ml vs 1.18 ml-post), greater annualized T2 lesion volume increase (0.0 ml vs 0.23 ml-post), lower brain parenchymal fraction (86.4% vs 85.7%-post) and greater annualized brain volume loss (-0.12% vs.-1.44%-post) compared with early pre-pregnancy period (all p>0.001). Forty-one women with available MRI data in late post-pregnancy (late-post) period had similar T2 lesion volume (1.18 ml vs 1.16 ml-late-post; p=0.14) and higher brain parenchymal fraction (85.6% vs. 86.0%-late-post; p=0.007) compared to early post-partum period.

Conclusions

The early post-partum period was associated with a transient increase in T2 lesion volume and accelerated brain volume loss compared to the pre-pregnancy period. In a proportion of women, newly accumulated T2 lesion volume and decreased brain parenchymal fraction did not return to its pre-pregnancy levels. These findings argue against any general protective effect of pregnancy on MS.