B cell depletion therapy does not resolve chronic active multiple sclerosis lesionsResearch in context
Pietro Maggi,
Colin Vanden Bulcke,
Edoardo Pedrini,
Céline Bugli,
Amina Sellimi,
Maxence Wynen,
Anna Stölting,
William A. Mullins,
Grigorios Kalaitzidis,
Valentina Lolli,
Gaetano Perrotta,
Souraya El Sankari,
Thierry Duprez,
Xu Li,
Peter A. Calabresi,
Vincent van Pesch,
Daniel S. Reich,
Martina Absinta
Affiliations
Pietro Maggi
Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Neuroinflammation Imaging Lab (NIL), Université Catholique de Louvain, Brussels, Belgium; Centre Hospitalier Universitaire Vaudois, Université de Lausanne, Lausanne, Switzerland; Corresponding author. Cliniques Universitaires Saint-Luc, Av. Hippocrate 10, 1200, Brussels, Belgium.
Colin Vanden Bulcke
Neuroinflammation Imaging Lab (NIL), Université Catholique de Louvain, Brussels, Belgium
Edoardo Pedrini
Institute of Experimental Neurology, Division of Neuroscience, Vita-Salute San Raffaele University and IRCCS San Raffaele Hospital, Milan, Italy
Céline Bugli
Plateforme Technologique de Support en Méthodologie et Calcul Statistique, Université Catholique de Louvain, Brussels, Belgium
Amina Sellimi
Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
Maxence Wynen
Neuroinflammation Imaging Lab (NIL), Université Catholique de Louvain, Brussels, Belgium
Anna Stölting
Neuroinflammation Imaging Lab (NIL), Université Catholique de Louvain, Brussels, Belgium
William A. Mullins
Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, USA
Grigorios Kalaitzidis
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Valentina Lolli
Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium
Gaetano Perrotta
Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium
Souraya El Sankari
Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
Thierry Duprez
Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
Xu Li
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Peter A. Calabresi
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Vincent van Pesch
Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
Daniel S. Reich
Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, USA
Martina Absinta
Institute of Experimental Neurology, Division of Neuroscience, Vita-Salute San Raffaele University and IRCCS San Raffaele Hospital, Milan, Italy; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Corresponding author. Vita-Salute San Raffaele University and IRCCS San Raffaele Hospital, Via Olgettina, 60, 20132, Milan, Italy.
Summary: Background: Chronic active lesions (CAL) in multiple sclerosis (MS) have been observed even in patients taking high-efficacy disease-modifying therapy, including B-cell depletion. Given that CAL are a major determinant of clinical progression, including progression independent of relapse activity (PIRA), understanding the predicted activity and real-world effects of targeting specific lymphocyte populations is critical for designing next-generation treatments to mitigate chronic inflammation in MS. Methods: We analyzed published lymphocyte single-cell transcriptomes from MS lesions and bioinformatically predicted the effects of depleting lymphocyte subpopulations (including CD20 B-cells) from CAL via gene-regulatory-network machine-learning analysis. Motivated by the results, we performed in vivo MRI assessment of PRL changes in 72 adults with MS, 46 treated with anti-CD20 antibodies and 26 untreated, over ∼2 years. Findings: Although only 4.3% of lymphocytes in CAL were CD20 B-cells, their depletion is predicted to affect microglial genes involved in iron/heme metabolism, hypoxia, and antigen presentation. In vivo, tracking 202 PRL (150 treated) and 175 non-PRL (124 treated), none of the treated paramagnetic rims disappeared at follow-up, nor was there a treatment effect on PRL for lesion volume, magnetic susceptibility, or T1 time. PIRA occurred in 20% of treated patients, more frequently in those with ≥4 PRL (p = 0.027). Interpretation: Despite predicted effects on microglia-mediated inflammatory networks in CAL and iron metabolism, anti-CD20 therapies do not fully resolve PRL after 2-year MRI follow up. Limited tissue turnover of B-cells, inefficient passage of anti-CD20 antibodies across the blood–brain-barrier, and a paucity of B-cells in CAL could explain our findings. Funding: Intramural Research Program of NINDS, NIH; NINDS grants R01NS082347 and R01NS082347; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Cariplo Foundation (grant #1677), FRRB Early Career Award (grant #1750327); Fund for Scientific Research (FNRS).
