Open Access

Brian C. Zhang, Tilman Schneider-Hohendorf, Rebecca Elyanow, Beatrice Pignolet, Simon Falk, Christian Wünsch, Marie Deffner, Erik Yusko, Damon May, Daniel Mattox, Eva Dawin, Lisa Ann Gerdes, Florence Bucciarelli, Lisa Revie, Gisela Antony, Sven Jarius, Christiane Seidel, Makbule Senel, Stefan Bittner, Felix Luessi, Joachim Havla, Matthias Knop, Manuel A. Friese, Susanne Rothacher, Anke Salmen, Fumie Hayashi, Roland Henry, Stacy Caillier, Adam Santaniello, Jessa Alexander, Riley Bove, Sergio Baranzini, Bruce A. C. Cree, Eduardo Caverzasi, Richard Cuneo, Stacy J. Caillier, Tiffany Cooper, Ari J. Green, Chu-Yueh Guo, Jeffrey M. Gelfand, Refujia Gomez, Sasha Gupta, Jill Hollenbach, Meagan Harms, Roland G. Henry, Stephen L. Hauser, Myra Mendoza, Jorge R. Oksenberg, Nico Papinutto, Sam Pleasure, Adam Santaniello, Joseph J. Sabatino, William A. Stern, Michael R. Wilson, Scott Zamvil, Orhan Aktas, Antje Giede-Jeppe, Barbara Gisevius, Markus Kowarik, Friedemann Paul, Veit Rothhammer, Corinna Trebst, Uwe Zettl, Maria Seipelt, Christoph Heesen, Sandra Nischwitz, Antonios Bayas, Hayrettin Tumani, Florian Then Bergh, Gerd Meyer zu Hörste, Tania Kümpfel, Catharina C. Gross, Brigitte Wildemann, Martin Kerschensteiner, Ralf Gold, Sven G. Meuth, Frauke Zipp, Bruce A. C. Cree, Jorge Oksenberg, Michael R. Wilson, Stephen L. Hauser, Scott S. Zamvil, Luisa Klotz, Roland Liblau, Harlan Robins, Joseph J. Sabatino, Heinz Wiendl, Nicholas Schwab

• Background: Glatiramer acetate (GA) is a well-tolerated treatment for multiple sclerosis (MS) and comparable in its efficacy to high-dose interferon beta (IFN). As a lack of validated treatment response biomarkers for MS hampers progress in personalised treatment, the study goal was to search for biomarkers of a successful treatment response utilising the known observation of T-cell expansions after GA treatment. Methods: T-cell receptor beta chain (TRB) sequencing was performed in 3021 patients with MS: a discovery cohort of 1627 patients with MS, 204 of whom had previously been treated with GA, and then validated in 1394 patients with MS, 424 of whom had previously been treated with GA. Clinical data from 1987 patients with MS treated with GA or IFN and available HLA information from the NationMS, ACP, EPIC, BIONAT, and CombiRx trial cohorts were used for a subsequent analysis. Findings: Common GA-associated TRB expansions were exclusively detected in HLA-A∗03:01 or inBackground: Glatiramer acetate (GA) is a well-tolerated treatment for multiple sclerosis (MS) and comparable in its efficacy to high-dose interferon beta (IFN). As a lack of validated treatment response biomarkers for MS hampers progress in personalised treatment, the study goal was to search for biomarkers of a successful treatment response utilising the known observation of T-cell expansions after GA treatment. Methods: T-cell receptor beta chain (TRB) sequencing was performed in 3021 patients with MS: a discovery cohort of 1627 patients with MS, 204 of whom had previously been treated with GA, and then validated in 1394 patients with MS, 424 of whom had previously been treated with GA. Clinical data from 1987 patients with MS treated with GA or IFN and available HLA information from the NationMS, ACP, EPIC, BIONAT, and CombiRx trial cohorts were used for a subsequent analysis. Findings: Common GA-associated TRB expansions were exclusively detected in HLA-A∗03:01 or in HLA-DRB1∗15:01 backgrounds, within CD8+ effector- or CD4+ central-memory T cells. Both sets of common sequences clonally expanded after GA treatment in a first validation cohort and predicted GA exposure in two further validation cohorts. To evaluate whether restriction of public TRBs to only two HLA alleles is also associated with GA's clinical efficacy, we analysed five cohorts of patients with MS for a potential benefit of the two HLAs concerning the GA response compared to IFN. We consistently found positive interactions with HLA-A∗03:01. This included a relative reduction in relapse risk compared to IFN in HLA-A∗03:01 carriers of 33% (CombiRx: GA + IFN arm: HR 0.67 [95% CI: 0.47-0.96], p = 0.0269) and 34% (CombiRx: GA arm: HR 0.66 [95% CI: 0.45-0.98], p = 0.0377), and in risk to first relapse of 63% (NationMS: HR 0.37 [95% CI: 0.16-0.88], p = 0.0246), but no positive association with DRB1∗15:01. Interpretation: HLA-A∗03:01 carrying patients with MS specifically benefit from GA treatment and GA significantly outperforms IFN in these patients. Therefore, determining HLA-A∗03:01 status before choosing a platform treatment for MS, would allow for a personalised treatment decision between GA and IFN.…