Biomarkers of response to ocrelizumab in relapsing-remitting multiple sclerosis.

To ascertain the changes of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) values in relapsing-remitting multiple sclerosis (RRMS) patients treated with ocrelizumab and their association with treatment response. Multicenter prospective study including 115 RRMS patients initiating ocrelizumab treatment between February 2020 and March 2022 followed during a year. Serum samples were collected at baseline and every 3 months to measure sNfL and sGFAP levels using single-molecule array (SIMOA) technology. Based on age and body mass index, sNfL values were standardized using z-score. NEDA (non-evidence of disease activity)-3 status was defined for patients free of disease activity after a year of follow-up. Inflammation (INFL) was considered when new relapses occurred during follow-up or new MRI lesions were found at 1-year exploration. PIRA (progression independent of relapse activity) was defined as disability progression occurring in the absence of relapses or new MRI activity. After a year on ocrelizumab, 85 patients (73.9%) achieved NEDA-3. Thirty patients did not achieve NEDA: 20 (17.4%) because of INFL and 10 (8.7%) because of PIRA. Of INFL patients, 6 (30.0%) had relapses, and 17 (85.0%) had at least one new MRI lesion at the 12-month examination. At baseline, INFL patients had higher sNfL (p = 0.0003) and sGFAP (p = 0.03) than the NEDA-3 group. PIRA patients mostly exhibited low sNfL and heterogeneous sGFAP levels. After a year, NEDA-3 and INFL patients showed similar decreases in sNfL (p < 0.0001) and sGFAP (p < 0.0001 for NEDA-3 and p = 0.001 for INFL ones). However, the decrease occurred earlier in NEDA-3 patients. Accordingly, sNfL > 1.5 z-score 3 months after ocrelizumab initiation indicated a higher risk of inflammation (OR = 13.6; p < 0.0001). Decrease in sGFAP values occurred later in both groups, with significant reductions observed at 12 months for INFL and 6 and 12 months for NEDA-3. No significant changes in sNfL or sGFAP were observed in PIRA patients. Ocrelizumab induced normalization of sNfL and sGFAP in the majority of NEDA-3 and inflammatory patients but did not cause changes in the PIRA group. Our data suggest that normalization of sNfL and sGFAP is associated with the lack of inflammatory-associated disease progression but it may not affect non-inflammatory PIRA.

Rodríguez-Jorge F ，Fernández-Velasco JI ，Villarrubia N ，Gracia-Gil J ，Fernández E ，Meca-Lallana V ，Díaz-Pérez C ，Sainz de la Maza S ，Pacheco EM ，Quiroga A ，Ramió-Torrentà L ，Martínez-Yélamos S ，Bau L ，Monreal E ，López-Real A ，Rodero-Romero A ，Borrega L ，Díaz S ，Eguía P ，Espiño M ，Chico-García JL ，Barrero FJ ，Martínez-Ginés ML ，García-Domínguez JM ，De la Fuente S ，Moreno I ，Sainz-Amo R ，Mañé-Martínez MA ，Caminero A ，Castellanos F ，Gómez López A ，Labiano-Fontcuberta A ，Ayuso L ，Abreu R ，Hernández MÁ ，Meca-Lallana J ，Martín-Aguilar L ，Muriel García A ，Masjuan J ，Costa-Frossard L ，Villar LM ... -  《Frontiers in Immunology》

Serum biomarkers at disease onset for personalized therapy in multiple sclerosis.

The potential of combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict disability worsening in multiple sclerosis (MS) remains underexplored. We aimed to investigate whether sNfL and sGFAP values identify distinct subgroups of patients according to the risk of disability worsening and their response to disease-modifying treatments (DMTs). This multicentre study, conducted across thirteen European hospitals, spanned from July 15, 1994, to August 18, 2022, with follow-up until September 26, 2023. We enrolled MS patients who had serum samples collected within 12 months from disease onset and before initiating DMTs. Multivariable regression models were used to estimate the risk of relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and Expanded Disability Status Scale (EDSS) score of 3. Of the 725 patients included, median age was 34.2 years (IQR, 27.6-42.4), and 509 patients (70.2%) were female. Median follow-up duration was 6.43 years (IQR, 4.65-9.81). Higher sNfL values associated with an elevated risk of RAW (HR of 1.45; 95% CI 1.19-1.76; P < 0.001), PIRA (HR of 1.43; 95% CI 1.13-1.81; P = 0.003), and reaching an EDSS of 3 (HR of 1.55; 95% CI 1.29-1.85; P < 0.001). Moreover, higher sGFAP levels were linked to a higher risk of achieving an EDSS score of 3 (HR of 1.36; 95% CI 1.06-1.74; P = 0.02) and, in patients with low sNfL values, to PIRA (HR of 1.86; 95% CI 1.01-3.45; P = 0.04). We further examined the combined effect of sNfL and sGFAP levels. Patients with low sNfL and sGFAP values (NLGL) exhibited a low risk of all outcomes and served as reference. Untreated patients with high sNfL levels showed a higher risk of RAW, PIRA, and reaching an EDSS of 3. Injectable or oral DMTs reduced the risk of RAW in these patients but failed to mitigate the risk of PIRA and reaching an EDSS of 3. Conversely, high-efficacy DMTs counteracted the heightened risk of these outcomes, except for the risk of PIRA in patients with high sNfL and sGFAP levels. Patients with low sNfL and high sGFAP values (NLGH) showed an increased risk of PIRA and achieving an EDSS of 3, which remained unchanged with either high-efficacy or other DMTs. In conclusion, evaluating sNfL and sGFAP levels at disease onset in MS may identify distinct phenotypes associated with diverse immunological pathways of disability acquisition and therapeutic response.

Monreal E ，Fernández-Velasco JI ，Álvarez-Lafuente R ，Sainz de la Maza S ，García-Sánchez MI ，Llufriu S ，Casanova B ，Comabella M ，Martínez-Yélamos S ，Galimberti D ，Ramió-Torrentà L ，Martínez-Ginés ML ，Aladro Y ，Ayuso L ，Martínez-Rodríguez JE ，Brieva L ，Villarrubia N ，Eichau S ，Zamora J ，Rodero-Romero A ，Espiño M ，Blanco Y ，Saiz A ，Montalbán X ，Tintoré M ，Domínguez-Mozo MI ，Cuello JP ，Romero-Pinel L ，Ghezzi L ，Pilo de la Fuente B ，Pérez-Miralles F ，Quiroga-Varela A ，Rubio L ，Rodríguez-Jorge F ，Chico-García JL ，Sainz-Amo R ，Masjuan J ，Costa-Frossard L ，Villar LM ... -  《-》

Effect of Natalizumab on sNfL and sGFAP Levels in Multiple Sclerosis Patients.

Sainz-Amo R ，Rodero-Romero A ，Monreal E ，Chico-García JL ，Rodríguez-Jorge F ，Fernández-Velasco JI ，Villarrubia N ，Veiga-González JL ，de la Maza SS ，Masjuan J ，Costa-Frossard L ，Villar LM ... -  《-》

Ocrelizumab in Early-Stage Relapsing-Remitting Multiple Sclerosis: The Phase IIIb ENSEMBLE 4-Year, Single-Arm, Open-Label Trial.

Hartung HP ，Benedict RHB ，Berger T ，Bermel RA ，Brochet B ，Carroll WM ，Freedman MS ，Holmøy T ，Karabudak R ，Nos C ，Patti F ，Perrin Ross A ，Vanopdenbosch L ，Vollmer T ，Wuerfel J ，Clinch S ，Kadner K ，Kuenzel T ，Kulyk I ，Raposo C ，Thanei GA ，Killestein J ... -  《-》

In multiple sclerosis patients a single serum neurofilament light chain (sNFL) dosage is strongly associated with 12 months outcome: data from a real-life clinical setting.

Malucchi S ，Bava CI ，Valentino P ，Martire S ，Lo Re M ，Bertolotto A ，Di Sapio A ... -  《-》