H. Kropshofer
Novartis Pharma AG NEUROSCIENCE DU GDDAuthor Of 2 Presentations
FC04.03 - High plasma glial fibrillary acidic protein levels predict disability milestone EDSS 7 in non-active secondary progressive multiple sclerosis
Abstract
Background
Glial fibrillary acidic protein (GFAP) is released into the cerebrospinal fluid and blood upon astroglial injury and activation, one of the hallmarks of progressive multiple sclerosis (PMS). It is unclear whether blood GFAP levels are associated with disability accumulation in secondary progressive MS (SPMS).
Objectives
To explore GFAP as a prognostic biomarker of disability worsening in patients with active and/or non-active SPMS (aSPMS and/or naSPMS) in the Phase 3 EXPAND study.
Methods
In this post-hoc analysis from the EXPAND study, baseline (BL) GFAP was quantified in EDTA plasma samples using Single Molecule Array technology. GFAP was categorized as high/low based on the gender stratified 80 percentile. The effect of GFAP on time to Expanded Disability Status Scale [EDSS] 7 (wheelchair restricted) was assessed using a Cox regression model adjusted for age, gender, disease duration, treatment, relapses in the 24 months prior to study start, and BL EDSS. Subgroup analyses were conducted in patients with aSPMS/naSPMS (with/without relapses ≤24 months prior to study entry, and/or gadolinium-enhancing T1 lesions at BL) and were also stratified by gender.
Results
Samples were available for 1405 of the 1651 patients randomized in the EXPAND study; median GFAP levels (pg/mL) were 119.6 (male) and 141.4 (female). Overall, the risk of reaching EDSS 7 was higher in patients with high BL GFAP (96%: high vs low GFAP, [34/281, 12.1%] vs [54/1117, 4.8%]; HR 1.96 [1.27; 3.03]; p=0.0024). Interestingly, the increased risk of reaching EDSS 7 was mainly seen in females (23/169; 13.6%] vs [34/673; 5.1%]; HR 2.22 [1.30; 3.80]; p=0.0035), and not significant in males ([11/112, 9.8%] vs [20/444, 4.5%]; HR 1.45 [0.67; 3.12]; p=0.3457). Increase in risk of reaching EDSS 7 was mainly observed in naSPMS patients (high GFAP [14/133; 10.5%] vs low GFAP [22/570; 3.9%]; HR 3.40 [1.71; 6.75]; p=0.0005) and was not significant in aSPMS patients (high GFAP [20/144; 13.9%] vs low GFAP [30/521; 5.8%]; HR 1.58 [0.88; 2.82]; p=0.1250). However, associations between BL GFAP levels and time to 6-months confirmed disability progression showed similar trends, but were less pronounced.
Conclusions
Blood GFAP appears to be a prognostic biomarker of disability worsening. The relevance of the gender difference and the stronger correlations found in SPMS patients with non-active versus active disease needs further investigation.
PS09.05 - Value of serum neurofilament light chain levels as a biomarker of suboptimal treatment response in MS clinical practice
- Ö. Yaldizli
- P. Benkert
- A. Maceski
- M. Barakovic
- R. Todea
- A. Cagol
- S. Schaedelin
- G. Disanto
- J. Oechtering
- A. Orleth
- D. Rey
- T. Sinnecker
- R. Rahmanzadeh
- S. Zadic
- R. Galbusera
- L. Achtnichts
- S. Aeschbacher
- A. Chan
- D. Conen
- T. Derfuss
- O. Findling
- B. Fischer-Barnicol
- K. Hrusovsky
- H. Kropshofer
- P. Lalive
- J. Lieb
- J. Lorscheider
- P. Maggi
- C. Müller
- S. Müller
- Y. Naegelin
- J. Müller
- J. Oksenberg
- C. Pot
- R. Du Pasquier
- E. Radue
- A. Salmen
- J. Vehoff
- E. Waubant
- S. Wellmann
- H. Wiendl
- J. Wuerfel
- C. Zecca
- K. Berger
- C. Gobbi
- L. Kappos
- D. Leppert
- C. Granziera
- J. Kuhle
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.