Blood biomarkers for predicting disability worsening in progressive multiple sclerosis: a multinational, individual participant-level analysis
Ahmed Abdelhak, Franziska Bachhuber, Kiarra Ning, Pascal Benkert, W. John Boscardin, Aleksandra Maleska Maceski, Sabine Schaedelin, Lutz Achtnichts, Sebastian Finkener, Patrice H. Lalive, Marjolaine Uginet, Caroline Pot, Renaud Du Pasquier, Robert Hoepner, Andrew T. Chan, Claudio Gobbi, Chiara Zecca, Stefanie Müller, Patrick Roth, Cristina Granziera, Tanuja Chitnis, Evan Madill, Howard L. Weiner, Ari Green, Stephen L. Hauser, Bruce Cree, Tania Kümpfel, Joachim Havla, Thomas Skripuletz, Stefan Gingele, Makbule Şenel, Ioannis Vardakas, Daniela Taranu, Ulf Ziemann, Markus C. Kowarik, Ingo Kleiter, Muna‐Miriam Hoshi, Uwe K. Zettl, Axel Haarmann, Simon Thebault, Mark S. Freedman, Hailey Bergman, Ellen Iacobaeus, Mohsen Khademi, Diana Ferraro, Martina Cardi, Sara Mariotto, Manuel Comabella, Xavier Montalbán, Andreu Vilaseca-Jolonch, Eva Strijbis, Mark HJ Wessels, Joep Killestein, Bernhard Hemmer, Friederike Held, Finn Sellebjerg, Helene Højsgaard Chow, Roberto Álvarez‐Lafuente, María Inmaculada Domínguez‐Mozo, Harald Hegen, Klaus Berek, Florian Deisenhammer, Eric Thouvenot, Hanane Agherbi, Konrad Rejdak, Magda Gąsior, Dimitrios Tzanetakos, John S. Tzartos, Maria Pia Sormani, Irena Dujmović, Georgina Arrambide, Michael Khalil, Fredrik Piehl, Charlotte E. Teunissen, Jens Kühle, Hayrettin Tumani
Abstract
BACKGROUND AND OBJECTIVES: Biologically informative markers like glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) may help predict confirmed disability worsening (CDW) in multiple sclerosis (MS). However, data on the prognostic value of their blood concentrations in progressive MS (PMS) are limited, and there are substantial discrepancies in the published literature. This international collaboration uses individual participant data to define the prognostic value of serum GFAP and NfL in people with PMS (pwPMS). METHODS: Data were collected from BioMS-eu network centres and collaborating cohorts. pwPMS with primary progressive MS (PPMS) or secondary progressive MS (SPMS) with at least one GFAP value and at least three follow-up expanded disability status scale (EDSS) scores were included. The prognostic value of serum GFAP and NfL age- and sex-adjusted Z-scores for future CDW was evaluated using Cox regression models, accounting for sex, age, baseline disease duration and EDSS, and dominant treatment during follow-up. RESULTS: 1058 participants and 7530 encounters were included (median age 53 years (IQR: 44 to 59), 57% female, follow-up 4.6 years (2.9 to 8.4)) with median baseline GFAP of 0.74 (-0.10 to 1.55) and NfL of 0.64 (-0.36 to 1.51). 723 CDW events were recorded. Each GFAP Z-score increase was associated with ~10% higher CDW risk (adjusted HR (aHR) 1.107 (1.001 to 1.225), p=0.049). Results were mainly driven by SPMS participants (n=613, aHR 1.242 (1.073 to 1.438), p=0.004). Higher NfL Z-scores predicted CDW only in PPMS participants (1.236 (1.092 to 1.399), p=0.001). CONCLUSIONS: GFAP was a prognostic indicator for future CDW in pwPMS, especially in pwSPMS. On the other hand, NfL was predictive of CDW only in pwPPMS.