Cantonal Hospital St. Gallen
Department of Neurology

Author Of 2 Presentations

Reproductive Aspects and Pregnancy Late Breaking Abstracts

LB01.06 - Interrupting disease modifying treatment for pregnancy in multiple sclerosis – effect on disease activity and serum neurofilament light chain

Speakers
Presentation Number
LB01.06
Presentation Topic
Reproductive Aspects and Pregnancy
Lecture Time
10:00 - 10:12

Abstract

Background

Pregnancy in MS typically goes along with reduced disease activity in the third trimester, followed by an increase in relapse frequency postpartum. Neurofilament light chain levels in serum (NfL) is a specific biomarker of neuroaxonal injury. Increased NfL levels are associated with relapses and MRI activity, while disease modifying treatment (DMT) response is reflected by a decrease of NfL.

Objectives

The objective of this study was to evaluate whether interrupting DMT due to pregnancy leads to increased NfL levels in MS.

Methods

We investigated prospectively documented pregnancies in the Swiss MS Cohort Study. Serum samples were collected 6- or 12-monthly and were analyzed by Simoa NF-light® assay. Uni- and multivariable mixed effect models were used to investigate associations between clinical characteristics and longitudinal NfL levels.

Results

We investigated 72 pregnancies in 63 relapsing MS patients (median age 31.4; disease duration 7.1 years; EDSS 1.5 at last visit before birth). In total, 433 samples were included: 92 during pregnancy or up to initiation of DMT but max. 9 months postpartum (pregnancy/post-partum period, pp), 167 prior to pp and 174 after the pp. Four patients had no DMT before, during and after pregnancy. DMT was continued in 13/72 pregnancies (>6 months during pregnancy: 6 rituximab/ocrelizumab, 4 natalizumab, 1 interferon-beta 1a i.m., 1 fingolimod and 1 glatiramer acetate). In univariable analysis, NfL levels were on average 22% higher during vs. outside the pp (β: 1.22, 95%CI: 1.10-1.35; p<0.001). We observed 29 relapses during the pp. In a multivariable analysis, relapses (within 120 days before serum sampling) were associated with 98% higher NfL (β: 1.98, 95%CI: 1.75-2.25; p<0.001); NfL was 7% higher per EDSS step increase (β: 1.07, 95%CI: 1.01-1.12; p=0.013) and on average 13% higher during vs. outside the pp (β: 1.13, 95%CI: 1.03-1.24; p=0.009). The effect of the pp on NfL disappeared after including DMT exposure (yes/no) at the sampling timepoint to the model (β:1.07, 95%CI: 0.97-1.18; p=0.178). Patients sampled during DMT had on average 12% lower NfL levels compared to patients without (β:0.88, 95%CI: 0.79-0.98; p=0.019).

Conclusions

Higher NfL levels were found during pp. This increase was independent of relapses suggesting increased subclinical disease activity during this time span. After including DMT into the model the effect of pregnancy on NfL disappeared: strategies allowing to continue DMT during pregnancy may be warranted.

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Biomarkers and Bioinformatics Oral Presentation

PS09.05 - Value of serum neurofilament light chain levels as a biomarker of suboptimal treatment response in MS clinical practice

Abstract

Background

Serum neurofilament light chain (sNfL) reflects neuro-axonal damage and may qualify as a biomarker of suboptimal response to disease modifying therapy (DMT).

Objectives

To investigate the predictive value of sNfL in clinically isolated syndrome (CIS) and relapsing-remitting (RR) MS patients with established DMT for future MS disease activity in the Swiss MS Cohort Study.

Methods

All patients were on DMT for at least 3 months. sNfL was measured 6 or 12-monthly with the NF-light®assay. The association between sNfL and age was modeled using a generalized additive model for location scale and shape. Z-scores (sNfLz) were derived thereof, reflecting the deviation of a patient sNfL value from the mean value of same age healthy controls (n=8865 samples). We used univariable mixed logistic regression models to investigate the association between sNfLz and the occurrence of clinical events (relapses, EDSS worsening [≥1.5 steps if EDSS 0; ≥1.0 if 1.0-5.5 or ≥0.5 if >5.5] in the following year in all patients, and in those fulfilling NEDA-3 criteria (no relapses, EDSS worsening, contrast enhancing or new/enlarging T2 lesions in brain MRI, based on previous year). We combined sNfLz with clinical and MRI measures of MS disease activity in the previous year (EDA-3) in a multivariable mixed logistic regression model for predicting clinical events in the following year.

Results

sNfL was measured in 1062 patients with 5192 longitudinal samples (median age 39.7 yrs; EDSS 2.0; 4.1% CIS, 95.9% RRMS; median follow-up 5 yrs). sNfLz predicted clinical events in the following year (OR 1.21 [95%CI 1.11-1.36], p<0.001, n=4624). This effect increased in magnitude with increasing sNfLz (sNfLz >1: OR 1.41 [95%CI 1.15-1.73], p=0.001; >1.5: OR 1.80 [95%CI 1.43-2.28], p<0.001; >2: OR 2.33 [95%CI 1.74-3.14], p<0.001). Similar results were found for the prediction of future new/enlarging T2 lesions and brain volume loss. In the multivariable model, new/enlarging T2 lesions (OR 1.88 [95%CI 1.13-3.12], p=0.016) and sNfLz>1.5 (OR 2.18 [95%CI 1.21-3.90], p=0.009) predicted future clinical events (n=853), while previous EDSS worsening, previous relapses and current contrast enhancement did not. In NEDA-3 patients, change of sNfLz (per standard deviation) was associated with a 37% increased risk of clinical events in the subsequent year (OR 1.37 [95%CI 1.04-1.78], p=0.025, n=587).

Conclusions

Our data support the value of sNfL levels, beyond the NEDA3 concept, for treatment monitoring in MS clinical practice.

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Author Of 5 Presentations

Biomarkers and Bioinformatics Poster Presentation

P0096 - Intrathecal immunoglobulin M synthesis is associated with higher disease activity and severity in Multiple Sclerosis (ID 1101)

Abstract

Background

Additional biomarkers reflecting disease activity and predicting severity of multiple sclerosis (MS) are urgently needed.

Objectives

To explore whether intrathecal immunoglobulin (Ig) M synthesis is associated with time from disease onset to first relapse, MS Severity Score (MSSS) and time to first initiation of high efficacy disease modifying treatments (DMT) in patients with relapsing MS in the Swiss Multiple Sclerosis Cohort study.

Methods

487patients were categorized by presence of CSF oligoclonal IgG bands (OCGB) and quantitative intrathecal IgG and IgM production (Intrathecal Fraction, IF). Treatments were classified according to "no therapy", "platform", "oral" and "high efficacy". Multivariable Cox proportional hazard models or a multivariable linear model, adjusted for relevant covariables, were used to assess time from disease onset to described endpoints and associations with the MSSS.

Results

OCGB were present in 89.3%, IgGIF in 66.3%, IgMIF in 26.9% and IgAIF in 11.9% of patients. Patients with IgMIF had a shorter interval from disease onset to first relapse (HR 1.887 [CI 1.181, 3.014], p<0.01) compared to those without OCGB and IgGIF and IgMIF. Quantitatively, patients with IgMIF above versus below the median had a 1.75- fold increased hazard of occurrence of a first relapse (HR 1.746 [CI 1.097, 2.781]; p=0.019). IgMIF positive patients had on average a 1.24 steps higher MSSS compared with those without any intrathecal Ig synthesis (estimate: 1.243 [CI 0.501,1.986], p<0.01), followed by patients with OCGB and quantitative production of IgGIF (estimate: 0.966 [CI 0.283, 1.650], p<0.01) and patients with only OCGB (estimate: 0.716 [CI -0.030, 1.461], p=0.060). Accordingly, patients with IgMIF production had a shorter interval to initiation of high efficacy DMT (HR 2.788 [CI 1.306, 5.951], p<0.01). Quantitatively, above versus below median IgMIF was associated with a 2.36-fold risk of escalation to a high efficacy DMT (HR 2.361 [CI 1.304, 4.277]; p<0.01).

Conclusions

In relapsing MS, presence of intrathecally produced IgM is associated with higher disease activity, more severe disease course and earlier use of high efficacy treatments. Intrathecally produced IgM may qualify as useful prognostic biomarker for therapeutic decision making in early stage of disease.

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Biomarkers and Bioinformatics Poster Presentation

P0097 - Intrathecal immunoglobulin M synthesis is associated with higher serum neurofilament light chain levels and increased MRI disease activity in MS (ID 1089)

Abstract

Background

Intrathecal IgM synthesis was reported to be associated with higher clinical disease activity and severity. We found an association also with earlier use of high efficacy treatments in relapsing MS (RMS).

Objectives

To explore whether patients with intrathecal IgM synthesis show a) higher serum neurofilament light chain levels (sNfL) as a reflection of neuronal damage, or b) signs of increased disease severity in cerebral MRI, in patients with RMS followed in the Swiss MS Cohort Study.

Methods

487 patients were categorized by presence of oligoclonal IgG bands (OCGB) and intrathecally produced IgG/M:

1) OCGB-/IgG-/IgM- (reference [ref]);

2) OCGB+/IgG-/IgM-;

3) OCGB+/IgG+/IgM- and

4) OCGB+/IgG+/IgM+.

sNfL was measured (at baseline and every 6- or 12 months) with the NF-light® assay. Age-dependent sNfL z-scores (sNfLz) were modelled in 8865 healthy control samples to reflect the deviation of a patient sNfL value compared to mean values observed in same age healthy controls. Yearly T2 lesion number and occurrence of new/enlarging T2 lesions were automatically assessed in cerebral MRIs and checked manually. Contrast enhancing lesions (CEL) were manually quantified. Linear or negative binomial mixed models were used to investigate the associations between the four CSF Ig patterns and longitudinal sNfLz and MRI measures, adjusted for DMT and other covariates.

Results

IgM+ patients had higher sNfLz vs reference (estimate 0.50 [CI 0.12, 0.89], p=0.011), whereas those with only OCGB+ (0.11 [-0.28, 0.50], p=0.582) or with OCGB+/IgG+ (0.20 [-0.16, 0.56], p=0.270) did not (n=2970 observations). This was confirmed when analyzing only untreated patients adjusting for T2 and CEL numbers (1.16 [0.47, 1.86], p<0.01 vs 0.58 [-0.11, 1.27], p=0.1022 vs 0.51 [-0.11, 1.13], p=0.108 vs ref, respectively) (n=234).

IgM+ patients had 2.28-fold more T2 lesions ([1.51, 3.44], p<0.01) vs ref; for patients with only OCGB+ (1.61 [1.07, 2.43], p=0.0237) or OCGB+/IgG+ (1.58 [CI 1.08, 2.32], p=0.0179) (n=1580) this association was weaker.

IgM+ was associated with a 2.47-fold risk for new/enlarging T2 lesions on yearly follow-up MRIs vs ref (2.47 [1.28, 4.78], p<0.01) but not the two other patient groups (1.84 [CI 0.93; 3.65], p=0.0799 and 1.61 [CI 0.87; 2.95], p=0.1280) (n=861).

Conclusions

Intrathecal IgM synthesis was consistently associated with quantitative measures of neuro-axonal injury and disease severity in RMS. Our findings strongly support the clinical utiliy of this biomarker.

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Biomarkers and Bioinformatics Poster Presentation

P0154 - Serum Neurofilament light chain captures and predicts disability progression independent of relapses (PIRA) in multiple sclerosis (ID 809)

Abstract

Background

In relapsing MS, blood NfL has emerged as a promising biomarker of disease activity and worsening. The ability of serum NfL (sNfL) to detect relapse-independent disability progression is less well established.

Objectives

We investigated whether patients followed in the Swiss Multiple Sclerosis Cohort (SMSC) without any relapses during follow-up, had higher sNfL levels when experiencing confirmed disability progression independent of relapses (PIRA) as compared to stable patients. Secondly, we explored whether baseline (BL) sNfL could predict PIRA.

Methods

BL and 6- or 12-monthly follow-up sNfL were measured by Simoa NF-light® assay in 4608 samples from 806 relapse-free MS patients and 8865 serum samples from 4133 healthy controls (median age 45 yrs). Age-dependent sNfL z-scores (sNfLz) were modeled in healthy controls using a generalised additive model for location scale and shape to reflect the deviation of a patient sNfL value from the mean value of same age healthy controls. PIRA was defined as an EDSS increase of ≥1.5 steps if baseline EDSS 0, ≥1.0 if 1.0-5.5, or ≥0.5 if >5.5, confirmed after ≥6 months. We used mixed effects models to investigate the association between PIRA, clinical parameters, disease modifying treatment, and log(sNfL) as dependent variable at each sampling. The predictive value of BL sNfLz was investigated by uni- and multivariable Cox proportional hazards models.

Results

806 (4608 samples) of 1399 patients in the SMSC did not experience relapses during a median follow-up of 4.7 years (57.6%; BL: 715 RRMS, 43 SPMS, 48 PPMS; median age 42 yrs; samples/patient: 5; EDSS 2.0). PIRA occurred in 153/806 (19.0%). In a multivariable model, sNfL was positively associated with age (1.7%/year [95%CI 1.5;2.0], p<0.001) and EDSS at BL (7.6%/step, [5.8;9.6], p<0.001), whereas it was decreased when sampled during monoclonal antibody therapy (-10.8%, [-14.7;-6.6], p<0.001) or oral MS treatments (-10.4%, [-14.1;-6.5%], p<0.001) as compared to untreated timepoints. Importantly, patients experiencing PIRA had 11.6% higher sNfL levels, compared with stable patients (4.5;19.2, p=0.001). The hazard of future PIRA increased by 23.5% (8.3;40.8, p=0.002) per 1 standard deviation higher BL sNfLz. This finding was confirmed after adjusting for age, EDSS score and treatment at BL (27.8%, [11.5;46.5], p<0.001; sNfLz > 2: 2.5-fold risk [95%CI 1.7-3.9], p<0.001 for PIRA event vs. sNfLz < 2).

Conclusions

Our data support the value of sNfL to capture and predict neuro-axonal injury leading to disability progression independent from relapses.

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Biomarkers and Bioinformatics Poster Presentation

P0160 - Serum NfL z-scores derived from a large healthy control group reflect different levels of treatment effect in a real-world setting (ID 916)

Abstract

Background

Serum neurofilament light chain (sNfL) levels reflect neuroaxonal damage and relate to disease activity in MS. sNfL may qualify as well as a biomarker of suboptimal treatment response to disease modifying therapies (DMT). Establishment of age-dependent reference ranges in healthy controls is a prerequisite for developing this biomarker for clinical use.

Objectives

To compare on-treatment sNfL levels with values from a healthy control cohort and to investigate the effect of DMTs on sNfL levels in patients from the Swiss MS Cohort Study.

Methods

sNfL was measured (at baseline and every 6- or 12 months) with the NF-light® assay. Age-dependent sNfL z-scores (sNfLz) were modeled in healthy controls using a generalized additive model for location scale and shape to reflect the deviation of a patient sNfL value from the mean value of same age healthy controls. Linear mixed models were used to investigate the associations between clinical characteristics, DMT and longitudinal sNfLz. Interaction terms and splines were used to model sNfLz and for comparison log(NfL), and their dynamics under treatment.

Results

sNfL was measured in 1368 patients with 7550 longitudinal samples (baseline: median age: 41.9 yrs; 5.4% CIS, 83.2% RRMS, 5.6% SPMS, 5.8% PPMS; median EDSS: 2.0; median follow-up: 4.6 yrs) and 4133 healthy controls with 8865 samples (median age: 44.8 yrs). In the multivariable model, sNfLz increased with EDSS (0.131/step, [95% CI 0.101;0.161]), recent (<120 days) relapse (0.739 [0.643;0.835]) decreased with age (-0.014/year [-0.02;-0.009]), and time on DMT (-0.040/year [-0.054;-0.027]); sNfLz were lower when sampled while on more effective DMT (oral versus platform injectables: -0.229 [-0.344;-0.144]; monoclonal antibodies (mAB) versus platform injectables: -0.349 [-0.475;-0.224]), (p<0.001 for all associations). sNfLz were inversely associated with the hierarchy in efficacy of mAB over orals and orals over platform therapies with regard to slope and extent of decrease (interaction between time under DMT and DMT class: p<0.001). sNfLz, but not log(NfL) showed normalization of sNfL levels by mAB to healthy control levels.

Conclusions

The dynamic change of sNfLz on DMT reflects closely their relative clinical efficacy and is more meaningful than log(sNfL) by excluding age as a confounding factor. Use of sNfLz based on a large normative database as an age-independent sNfL measure improves the accuracy of the sNfL signal and hence their clinical utility.

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Imaging Poster Presentation

P0638 - Role of Gadolinium-based contrast agents to detect subclinical disease activity in clinically stable patients in the Swiss MS Cohort Study (ID 821)

Abstract

Background

Gadolinium (Gd)-based contrast agents are widely used to assess disease activity and treatment response by MRI in multiple sclerosis (MS). There is, however, increasing concern about their safety as their repeated administration may lead to brain parenchymal accumulation, while preclinical models suggest that they induce mitochondrial toxicity and neuronal cell death. Moreover, recent reports have demonstrated that three-dimensional (3D) T2-weighted Fluid-Attenuated-Inversion-Recovery (FLAIR) is highly sensitive in detecting new or enlarging MS lesions.

Objectives

To explore whether the presence of contrast enhancing lesions (CEL) based on Gd injection is more sensitive in detecting lesional activity in clinically stable MS patients in comparison to the analysis of new or enlarging MS lesions by 3D FLAIR.

Methods

MS patients being part of the observational, multicenter Swiss Multiple Sclerosis Cohort Study (SMSC) with contrast enhanced T1-weighted (T1w) images were included. Clinical stability was defined as no relapse and no Expanded Disability Status Scale (EDSS) increase during at least twelve months prior to MRI. Presence of CEL was assessed on contrast enhanced T1w images. Presence of new or enlarging T2w lesions was assessed manually on 3D FLAIR in an independent analysis by a different investigator in clinically stable MS patients presenting with CEL.

Results

3930 MRI scans (3.0 Tesla n=1497 (38%)) in 1057 participants (685 women, median age 42.0 years, 941 with relapsing MS, 116 with progressive MS, median EDSS 2.0 (range 1.5-3.5), median disease duration 7.4 years) were included.

Of 2620 MRI scans (66.7%) acquired in clinically stable conditions 46 (1.8%) demonstrated CEL. In all of these, new or enlarging T2w lesions were detectable by 3D FLAIR when a previous MRI was available for comparison (previous MRI available in 29/46; median number of new or enlarging T2w lesions: 3 (range 1-41, total number 176); median number of CEL: 1 (range 1-4, total number 47)).

Conclusions

In our large cohort from clinical practice, the assessment of new or enlarging lesions by 3D FLAIR was equally sensitive as the quantification of CEL to detect disease activity in clinically stable MS patients, challenging current practice of the use of Gd-enhanced MRI for monitoring of MS in clinical routine.

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