San Luigi Gonzaga Hospital
SCDO Neurologia

Author Of 2 Presentations

Observational Studies Oral Presentation

PS01.04 - Comparison of disability trajectories in relapsing Multiple Sclerosis patients treated with early intensive or escalation treatment strategies

Abstract

Background

to date, no consensus exists on how aggressively and timely treat relapsing-remitting multiple sclerosis (RRMS) patients.

Objectives

To evaluate disability trajectories in a cohort of RRMS patients stratified according to two different disease modifying therapy (DMT) strategies, early intensive treatment (EIT) or moderate-efficacy treatment followed by escalation to higher-efficacy DMT (ESC).

Methods

RRMS patients with ≥5-year follow-up and ≥3 visits after start DMT, and a first visit within 3 years from disease onset were selected from the Italian MS Registry. EIT group included patients who received, as first DMT, fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group included those who received the high efficacy DMT after ≥1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score(PS)-matched for characteristics at the first DMT. The follow-up time from the first DMT start has been segmented into 12-month periods. The disability trajectories were evaluated by applying a longitudinal model for repeated measures with an autoregressive variance-covariance structure. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual EDSS changes compared to baseline values (delta-EDSS) in EIT and ESC groups.

Results

The study cohort included 2,652 RRMS patients from 62 Italian MS centers. The PS matching procedure produced 365 pairs. The median (IQR) follow-up after the first DMT start was 8.5 (6.5–11.7) years. All of the ESC patients escalated to a higher-efficacy DMT after a median time of 5.1 (3.1–8.4) years. The estimated baseline EDSS with relative confidence interval (95% CI) value was 2.52 (2.33-2.71) in the ESC group and 2.45 (2.26-2.64) in the EIT group. Mean delta-EDSS at each 12 month period were all significantly (p<0.02) higher in the ESC group compared to the EIT group. In particular, the mean delta-EDSS differences between the two groups tend to increase from 0.1 (0.01-0.19, p=0.03) at 1 year to 0.30 (0.07-0.53, p=0.009) at 5 years and to 0.67 (0.31-1.03, p=0.0003) at 10 years.

Conclusions

Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression and the effect tends to increase over time despite patients in the ESC group escalated to a higher-efficacy DMT.

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Pediatric MS Oral Presentation

YI02.05 - Cognition and socio-professional attainment in paediatric onset multiple sclerosis: a reappraisal after 10 years

Abstract

Background

Cognitive impairment (CI) affects nearly 30% of paediatric patients with Multiple Sclerosis (MS) and has a negative impact on school performance and participation in social activities. This study is a re-appraisal of cognitive functioning and socio-professional attainment in adulthood in an Italian cohort of paediatric MS patients after 10 years from baseline neuropsychological assessment.

Objectives

To re-assess cognitive performance and its impact on socio-professional attainment in our cohort of paediatric MS patients after 10 years from baseline evaluation and to determine predictors of the individual outcomes.

Methods

Sixty-three paediatric patients were assessed at baseline and 48 followed-up after five years. To date, 31 out of these 48 patients (17 females, mean age 27.9±2.5 years, mean EDSS 1.7±1.6) were reassessed on an extensive neuropsychological battery and compared with a matched group of 31 healthy controls. CI was defined as the failure of > 2 tests. Socio-professional attainment was evaluated on the Work and Social Assessment Scale (WSAS). Predictors of CI and WSAS score were assessed through multivariable logistic and linear models.

Results

After a mean follow-up of 12.5±2.3 years, 15 (54%) subjects were classified as cognitively impaired. Patients with CI compared with those cognitively preserved at follow-up had higher Expanded Disability Status Scale (EDSS) score (1.9±1.4 vs 1.0±0.7; p = 0.046), lower baseline intelligence quotient (IQ) (86.2±23.8 vs 103.6±14.7; p = 0.025) and were less frequently treated with disease modifying therapy (DMT) at baseline [6 (35.3%) vs 11 (78.6%); p = 0.016]. In the regression model, CI after 10 years was related to lower IQ (OR 0.93, 95% CI 0.87-0.99, p = 0. 027) and absence of DMT at baseline assessment (OR 17.78 95%; 1.72-183.65, p = 0.017).

Baseline predictors of worse socio-professional attainment on the WSAS in adulthood were CI (B=6.3, p=0.016), higher EDSS (B=2.2, p=0.023) and higher age at onset (B=0.6, p=0.041). As for 10-year correlates, only CI was associated to poor functional outcome (B=5.2, p=0.006).

Conclusions

Complete data collection is ongoing; available findings to date show that in paediatric onset subjects CI remains significant in adulthood, is related to lower cognitive reserve, higher levels of neurological impairment and delay in DMT initiation. Moreover, CI plays a key role in predicting the subject social performance and professional outcome. Early treatment and promotion of strategies aimed at enhancing cognitive reserve are recommended in paediatric patients with MS.

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Author Of 7 Presentations

Biomarkers and Bioinformatics Late Breaking Abstracts

LB1219 - Normal serum NFL levels: a proposal of cut-off strategy definition for the clinical practice (ID 2090)

Speakers
Presentation Number
LB1219
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum Neurofilament light (sNFL) protein is the most promising marker of disease activity and treatment response in Multiple Sclerosis (MS). To implement sNFL in clinical practice, the definition of normal widely accepted values represents a crucial step still to be addressed. Clinically applicable cut-off values need to take into account age dependency; in addition, recent evidences suggest that physical parameters as body mass index (BMI) and blood volume (BV) might influence sNFL levels.

Objectives

The present study aims to address these crucial needs, describing sNFL levels in healthy population, their inter-individual variability in a short-term follow-up and defining reference cut-off values. The final objective is to define a strategy to allow implementation of sNFL in clinical practice.

Methods

We measured sNFL by single molecule array (Simoa) assay (NF-light advantage Kit, Quanterix) in 79 healthy individuals to define reference cut-off values. Age, BMI and BV were correlated with sNFL levels. In addition, sNFL were evaluated after a short-term follow-up time (median 67 days) to assess intra-individual variability: consecutive blood samples were tested in a subset of 27 participants (n=2-4 sample for each individual) and the coefficient of variation (CV) for NFL levels of each participant was evaluated.
sNFL were also tested in 23 naïve MS patients both at diagnostic time and immediately before treatment (median 76 days after) to evaluate the variability of sNFL in patients and the applicability of obtained cut-off values.

Results

1) Our data confirmed a strong correlation between sNFL levels and age. We found a negative correlation between sNFL levels and BV. 2) Short-term follow-up NFL assessments showed an overall intra-individual stability in sNFL levels in healthy population (median CV 15%). 3) We defined specific age decade-related cut-off values. 4) In naïve MS patients, sNFL levels were higher than control values; a high variability between diagnostic time and the beginning of treatment (median CV 39%) was shown. Cut-off values were applied in MS patients to discriminate high from normal sNFL levels: at diagnostic time, 57% of MS patients showed high sNFL levels, while at treatment start, 70% of patients demonstrated normal NFL values.

Conclusions

The present study suggests a strategy to define clinical applicable cut-offs to exploit sNFL as a personalised medicine tool in MS: specific cut-off values were calculated for each age decade. sNFL levels demonstrated an overall intra-individual stability in healthy participants in the short-term: this is relevant for a biomarker of disease activity and treatment response that, if successful, will be serially assessed during patients follow-up.

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Biomarkers and Bioinformatics Late Breaking Abstracts

LB1220 - Real-life experience with sNFL in Multiple Sclerosis patients, as monitoring and treatment decision biomarker   (ID 2091)

Speakers
Presentation Number
LB1220
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Neurofilament light chain (NFL) are the most promising biomarkers to investigate clinical activity and treatment efficacy in multiple sclerosis (MS), for which, to date, clinical examination and magnetic resonance imaging (MRI) are the only tools available for diagnosis and monitoring. NFL are released upon axonal damage in the cerebrospinal fluid and, in low concentration, in serum (sNFL). Whilst correlation between NFL and clinical outcomes is established, their implementation in clinical practice is still to be addressed.

Objectives

The aim of the present real-life cross-sectional study is to describe sNFL in a large cohort of MS patients as additional measure of disease activity and treatment efficacy.

Methods

We measured sNF-L by single molecule array (Simoa) assay (NF-light advantage kit, Quanterix) in 79 healthy participants and in 961 MS patients (n=1130 samples). sNFL were cross-sectionally evaluated in 830 relapsing remitting (RR), 53 primary progressive (PP) and 78 secondary progressive (SP) MS patients at different disease stages including diagnostic time, immediately before treatment, and during treatment with the main disease modifying treatments (DMTs): Interferon-beta, Glatiramer acetate, DimethylFumarate, Teriflunomide, Natalizumab, Alemtuzumab, Fingolimod, anti-CD20 . Clinical assessment was performed to evaluate correlations between sNFL, MRI and relapses.

Results

1) We established clinically applicable cut-off values for each age decade testing healthy individuals, later used to interpret sNFL levels in individual MS patients. 2) Progressive MS patients showed higher sNF-L levels and a greater prevalence of high sNFL levels (32% in PPMS and 26% in SPMS) relative to RRMS patients (16%), with respect to the previously determined cut-off values. 3) Patients experiencing MRI and/or clinical activity close to NFL dosage (+/-60 days) showed higher levels than stable patients; according to cut-off values, high NFL levels were observed in a substantial percentage of MRI active patients (72%) and clinically active patients (75%). 4) All DMTs notably lower sNF-L in RRMS patients treated for more than 12 months relative to untreated patients; though, 12% of treated patients still demonstrated high NFL levels.

Conclusions

This study provides a real-life picture of sNFL in a large cohort of MS patients. Cut-off values specific for age decade were applied to discriminate patients samples in different contexts, showing correlation with disease subtype, clinical activity and DMTs efficacy. Our study shows that clinically applicable cut-offs can enable the implementation of sNFL in everyday clinical practice in individual patients, demonstrating its potential as monitoring and treatment decision biomarker.

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Biomarkers and Bioinformatics Late Breaking Abstracts

LB1221 - Applicability of sNFL in Multiple Sclerosis as additional measure in clinical practice and implications in NEDA-3 evaluation.   (ID 2092)

Speakers
Presentation Number
LB1221
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Despite the increased availability of efficient therapeutic options, early and effective intervention is still mandatory for successful clinical management in Multiple Sclerosis (MS). Speaking of which, a composite measure of disease status termed "no evidence of disease activity" (NEDA) has been proposed as target for treatment in MS. However, this definition needs to be implemented with biological measures for a more personalized medicine. Serum Neurofilament light chain (sNfL) represents the most promising biomarker of disease activity and treatment efficacy in MS, reflecting axonal damage in the central nervous system. To date, sNFL correlation with clinical outcomes is well established in group analysis, yet, its implementation for individual patients is still to be addressed.

Objectives

The aim of the present real-life study is to investigate sNFL as additional measure of treatment efficacy in NEDA-3 patients.

Methods

We measured sNF-L by single molecule array (Simoa) assay (NF-light advantage kit, Quanterix) in 79 healthy participants and in 582 cross-sectionally enrolled RRMS patients, including 61 naive patients, and 521 patients treated with first- or second line therapies, demonstrating NEDA-3 status (no relapses, no disability progression, no MRI activity) during at least 12 months.

Results

1) We established clinically applicable cut-off values for each age decade testing healthy individuals, later used to interpret sNF-L levels in MS patients. 2) In MS patients, treatments notably lower sNF-L relative to untreated patients. 3) According to cut-off values, 53/521 (10%) NEDA-3 patients still demonstrate high NFL levels. These patients were distinguished in different categories: a) patients showing borderline sNFL values; b) patients with concomitant pathologies; c) patients experiencing chronic ongoing fatigability (not classifiable as disability progression); d) patients with a very active disease history; e) patients with conceivable inflammation not detectable by RMN or clinics. 4) The percentage of NEDA-3 patients with high NFL lowers with the extension of NEDA-3 status duration (down to 5% in patients with NEDA-3 status longer than 8 years).

Conclusions

The present cross-sectional study identified a subgroup of NEDA-3 patients showing high sNFL levels. High pathological sNFL levels, reflecting axonal damage, suggest the presence of chronic disease activity or subclinical transitory active inflammation not detectable by RMN or clinics in NEDA-3 patients. The establishment of simple applicable cut-off values allows sNFL applicability in everyday clinical practice. In particular, sNFL could represent an additional measure to be included in NEDA assessment for monitoring therapeutic response in individual MS patients.

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Biomarkers and Bioinformatics Late Breaking Abstracts

LB1245 - BB-CRESM: a structured institutional biobank for quality research in Multiple Sclerosis. (ID 2131)

Speakers
Presentation Number
LB1245
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Biobanks have recently become an important tool in clinical research. The availability of biological samples collected and stored following strict quality standards is crucial in biomedical and translational research in Multiple Sclerosis (MS), to better understand disease pathogenesis, identify biomarkers of diagnosis, prognosis and treatment response.

The Regional Reference Multiple Sclerosis Center (CRESM) at the S. Luigi Gonzaga Hospital provides comprehensive care for more than 2000 MS patients. It has been operational since 2013 in transforming the reserve of biological samples into a structured biobank.

Objectives

To describe the establishment of a structured MS biobank starting from a collection of biological samples and the process for providing scientists with biological samples and associated data.

Methods

According to guidelines by the “Biobanking and Biomolecular Resources and Research Infrastructure” (BBMRI), the steps for the BB-CRESM establishment were: Institutional commitment; Biobank management and staffing; Development of procedures to address ethical, legal, and social issues, according to the General Data Protection Regulation, in collaboration with a bioethicist.

All technical procedures were included into Standard Operating Procedures manual.

Results

BB-CRESM is a structural part of the Piedmont Regional Health Service. The General Director of San Luigi Hospital approved its Regulation, selected the BB-CRESM director and the members of the Scientific Committee.

BB-CRESM is a non-profit organization supported by the Italian Multiple Sclerosis Foundation.

Specific protocols regulate the timing and modalities of biological sample collection, ensuring privacy of subjects.

A detailed description of the biobank is in-person explained to each patient or healthy subject with the help of a leaflet; following which the informed consent is obtained. The Ethical Committee approved both the leaflet and the informed consent model.

Scientists can apply to the director of BB-CRESM specifying number, types and quantity of required samples and data. The samples can be distributed if a) they are used for a research project approved by an Ethic Committee; b) the research project is approved by the Scientific Committee; c) the scientist signs the Material Transfer Agreement; d) scientist agrees to share crude data with BB-CRESM e) scientist contributes to BB-CRESM collection and shipment expenses.

Since 2013, more than 1000 participants (healthy controls and MS patients) have enrolled in the BB-CRESM; over 20000 tubes of biological material (cerebrospinal fluid, serum, plasma, PBMCs, RNA and DNA) have been collected and stored.

Conclusions

BB-CRESM collects, stores and distributes biological samples along with associated data ensuring quality of collection and bio-banking according to BBMRI.

MS researchers can contact BB-CRESM at biobanca.cresm@sanluigi.piemonte.it.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0286 - Alemtuzumab following natalizumab: a multicentric Italian real-world experience (ID 993)

Speakers
Presentation Number
P0286
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab was approved by EMA in 2013 for active relapsing-remitting multiple sclerosis patients (RRMS). The ideal candidate is an active patient in early phase of disease. iIn real world alemtuzumab is also used when many treatments before have failed. Patients with long-term natalizumab exposure and anti JCV seropositivity who stop natalizumab for the risk of PML are a category of patients for whom no specific therapeutic strategy has been established.

At present, neurologists have may highly active drugs but there are no head to head studies directly comparing the efficacy of alemtuzumab with other efficacious therapies and the decision to chose the most suitable medication depends on different factors, such as the potential side effects. In patients who stop natalizumab alemtuzumab can represent a choice.

Objectives

The aim ot this observational study was to evaluate the efficacy and safety of alemtuzumab when used in patients previously treated with natalizumab.

Methods

This is a multicentric retrospective observational study.

Study population is composed by 50 RRMS patients (18 male and 32 female) with a median EDSS of 2 (range 1-7) from five Italian Multiple Sclerosis Centres who stopped natalizumab treatment after a median number of 22 infusions (range 3-114).

Five out of 50 patients were JCV seronegative and in these patients decision to stop natalizumab was due to radiological activity during natalizumab (2 patients), hypertransaminasemia (2 patients), patient request (1 patient). 45 out of patients were JCV seropositive and for these patients reason for stopping was the risk of PML.

Switch to alemtuzumab was made after a median wash out period of 2 months (range 0,7-5 months).

Patients underwent brain MRI at the end of natalizumab treatment, at 6 and 12 months after alemtuzumab infusion.

Results

Brain MRI at six months after alemtuzumab was available for 48 out of 50 patients and in 43 of them neither signs of disease activity nor new lesions were present; 3 patients showed new lesions and 1 patient had radiological activity. No patient showed clinical activity.

Brin MRI at 12 months after alemtuzumab was available in 46 out of 50 patients and in 42 out of 46 there was no sign of disease activity. In 4 patients brain MRI showed disease activity (1 pt) or new lesions (2 pts ) or both (1 pt).

Clinical relapse after alemtuzumab therapy occurred in 1 out of 50 patients; this patient underwent the third infusion of drug.

No patient developed PML.

Conclusions

Alemtuzumab started shortly after natalizumab interruption was highly efficacious in controlling disease course, as 87% of patients showed no evidence of clinical and radiological activity one year after treatment starting.

The choice of alemtuzumab use in JCV seropositive patients must take in consideration the necessity to treat a very severe disease and the safety profile of the drug to which switching.

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Observational Studies Poster Presentation

P0913 - Risks associated with wash-out duration when switching from fingolimod to cell-depleting agents (ID 1317)

Abstract

Background

A wash-out duration lasting >1–2 months between the majority of sequential disease-modifying therapies (DMTs) is associated with an increased risk of disease reactivation in Multiple Sclerosis (MS) patients.

Fingolimod (FTY) induces sequestration of lymphocytes in secondary lymphoid organs and the average lymphocyte recovery following discontinuation takes 1-2 months. It has been hypothesized that the therapeutic effects of subsequent cell-depleting agents may be compromised if lymphocyte recovery is still incomplete and that shorter wash-out periods do not affect the disease reactivation risk.

Objectives

To assess the risk of relapses following FTY discontinuation and the initiation of a B/T cell-depleting agent initiation in relation to the duration of wash-out between the drugs using data from the Italian MS Registry.

Methods

Patients who initiated alemtuzumab, rituximab, ocrelizumab or cladribine within six months of FTY discontinuation, and with a follow-up of at least six months, or until a relapse occurred, were included in the study. The risk of relapses was assessed in relation to different wash-out durations (<6, 6-11, 12-17 and >/=18 weeks) using a Poisson regression analysis (and reported as incidence rate ratio - IRR) and a Cox proportional hazards model including age, disease duration, relapses during FTY treatment, EDSS and reason for FTY discontinuation as covariates.

Results

Inclusion criteria were met by 329 patients (226F, 103M; mean age 41±10 years). Following a median wash-out period of 11 weeks [IQR: 6-16], 175 patients started alemtuzumab, 69 rituximab, 68 ocrelizumab and 17 cladribine. Ninety patients relapsed during the wash-out period and 72 during the subsequent cell-depleting therapy. During the cell-depleting treatment, IRR for a relapse was significantly greater in patients with a washout-period of 12-17 (IRR (95%CI): 2.4 (1,1-5,5); p=0.037) and >/=18 weeks (6.0 (2.8-12.7); p<0.001) compared to the reference period (<6 weeks).

The multivariable Cox analysis showed that the time to a relapse was significantly influenced by the occurrence of relapses during FTY treatment (HR (95%CI): 1.4 (1.2-1.7); p<0.001). Moreover, wash-out durations of 6-11, 12-17 and >/=18 weeks were associated with a higher risk of a relapse in comparison to wash-out durations shorter than 6 weeks (3.8 (1.1-13.2); p=0.037; 6.0 (1.7-21.9); p=0.006; 16.3 (4.8-56.3); p<0.001, respectively).

Conclusions

The risk of relapses during a cell-depleting therapy following a sequestering agent, namely FTY, increases progressively with the duration of wash-out, underlining the need of a short wash-out period also in this type of treatment sequence.

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Reproductive Aspects and Pregnancy Poster Presentation

P1115 - A first characterization of placenta-derived extracellular vesicles in patients with multiple sclerosis. (ID 1909)

Speakers
Presentation Number
P1115
Presentation Topic
Reproductive Aspects and Pregnancy

Abstract

Background

Pregnancy is a condition of complex immunomodulation during which multiple sclerosis (MS) significantly improves. The molecular mechanisms behind this phenomenon have not been completely elucidated. A central role is played by the placenta and its released factors such as the extracellular vesicles (EV), a peculiar mechanism of communication and material exchange between cells. Studies conducted on an experimental murine model of MS have shown that EV shed into the blood during pregnancy have an inhibitory effect on the proliferation of T cells.

Objectives

To characterize the surface markers expressed by the EV secreted by the maternal (decidua) and fetal (trophoblast) side of the placenta of patients with MS and healthy donors (HC), and to evaluate the effects of the EV on the activation status of CD14+ monocytes and the activity of regulatory T lymphocytes (Treg).

Methods

Total EV shed by placental samples from 15 women with MS and 14 HC were isolated by ultracentrifugation, quantified by Nanoparticle Tracking Analysis and characterized by flow cytometry for the expression of 37 surface markers using the human MACSPlex Exosome Kit. CD14+ monocytes, Treg end CD4+ T cells were isolated from HC buffy coats. CD14+ monocytes were activated with LPS and the expression levels of pro and anti-inflammatory cytokines was evaluated by real-time PCR. CD4+ T cells were activated via CD3 and CD28 and their proliferation activity was evaluated by BrdU Cell Proliferation Assay after co-culture with EV-conditioned Treg.

Results

Most of the analyzed surface markers resulted differentially expressed between the EV released by decidua or trophoblast, but not between the EV shed by placental tissues of MS patients or HC, except for CD133, whose level was higher in the EV secreted by trophoblast of women with MS. The conditioning with EV shed by placenta samples of MS patients was able to moderately decrease the expression level of pro-inflammatory cytokines by activated CD14+ monocytes and the proliferation activity of CD4+ T cells, although the effect was not statistically significant.

Conclusions

For the first time to our knowledge, this study enabled a preliminary characterization of the EV shed by placental tissues of patients with MS. However, further studies are needed to clarify the role of placental EV in the pregnancy-related improvement of the MS disease.

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Presenter Of 1 Presentation

Biomarkers and Bioinformatics Late Breaking Abstracts

LB1221 - Applicability of sNFL in Multiple Sclerosis as additional measure in clinical practice and implications in NEDA-3 evaluation.   (ID 2092)

Speakers
Presentation Number
LB1221
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Despite the increased availability of efficient therapeutic options, early and effective intervention is still mandatory for successful clinical management in Multiple Sclerosis (MS). Speaking of which, a composite measure of disease status termed "no evidence of disease activity" (NEDA) has been proposed as target for treatment in MS. However, this definition needs to be implemented with biological measures for a more personalized medicine. Serum Neurofilament light chain (sNfL) represents the most promising biomarker of disease activity and treatment efficacy in MS, reflecting axonal damage in the central nervous system. To date, sNFL correlation with clinical outcomes is well established in group analysis, yet, its implementation for individual patients is still to be addressed.

Objectives

The aim of the present real-life study is to investigate sNFL as additional measure of treatment efficacy in NEDA-3 patients.

Methods

We measured sNF-L by single molecule array (Simoa) assay (NF-light advantage kit, Quanterix) in 79 healthy participants and in 582 cross-sectionally enrolled RRMS patients, including 61 naive patients, and 521 patients treated with first- or second line therapies, demonstrating NEDA-3 status (no relapses, no disability progression, no MRI activity) during at least 12 months.

Results

1) We established clinically applicable cut-off values for each age decade testing healthy individuals, later used to interpret sNF-L levels in MS patients. 2) In MS patients, treatments notably lower sNF-L relative to untreated patients. 3) According to cut-off values, 53/521 (10%) NEDA-3 patients still demonstrate high NFL levels. These patients were distinguished in different categories: a) patients showing borderline sNFL values; b) patients with concomitant pathologies; c) patients experiencing chronic ongoing fatigability (not classifiable as disability progression); d) patients with a very active disease history; e) patients with conceivable inflammation not detectable by RMN or clinics. 4) The percentage of NEDA-3 patients with high NFL lowers with the extension of NEDA-3 status duration (down to 5% in patients with NEDA-3 status longer than 8 years).

Conclusions

The present cross-sectional study identified a subgroup of NEDA-3 patients showing high sNFL levels. High pathological sNFL levels, reflecting axonal damage, suggest the presence of chronic disease activity or subclinical transitory active inflammation not detectable by RMN or clinics in NEDA-3 patients. The establishment of simple applicable cut-off values allows sNFL applicability in everyday clinical practice. In particular, sNFL could represent an additional measure to be included in NEDA assessment for monitoring therapeutic response in individual MS patients.

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