Baseline Inflammatory Status Reveals Dichotomic Immune Mechanisms Involved In Primary-Progressive Multiple Sclerosis Pathology.

To ascertain the role of inflammation in the response to ocrelizumab in primary-progressive multiple sclerosis (PPMS). Multicenter prospective study including 69 patients with PPMS who initiated ocrelizumab treatment, classified according to baseline presence [Gd+, n=16] or absence [Gd-, n=53] of gadolinium-enhancing lesions in brain MRI. Ten Gd+ (62.5%) and 41 Gd- patients (77.4%) showed non-evidence of disease activity (NEDA) defined as no disability progression or new MRI lesions after 1 year of treatment. Blood immune cell subsets were characterized by flow cytometry, serum immunoglobulins by nephelometry, and serum neurofilament light-chains (sNfL) by SIMOA. Statistical analyses were corrected with the Bonferroni formula. More than 60% of patients reached NEDA after a year of treatment, regardless of their baseline characteristics. In Gd+ patients, it associated with a low repopulation rate of inflammatory B cells accompanied by a reduction of sNfL values 6 months after their first ocrelizumab dose. Patients in Gd- group also had low B cell numbers and sNfL values 6 months after initiating treatment, independent of their treatment response. In these patients, NEDA status was associated with a tolerogenic remodeling of the T and innate immune cell compartments, and with a clear increase of serum IgA levels. Baseline inflammation influences which immunological pathways predominate in patients with PPMS. Inflammatory B cells played a pivotal role in the Gd+ group and inflammatory T and innate immune cells in Gd- patients. B cell depletion can modulate both mechanisms.

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Copyright © 2022 Fernández-Velasco, Monreal, Kuhle, Meca-Lallana, Meca-Lallana, Izquierdo, Oreja-Guevara, Gascón-Giménez, Sainz de la Maza, Walo-Delgado, Lapuente-Suanzes, Maceski, Rodríguez-Martín, Roldán, Villarrubia, Saiz, Blanco, Diaz-Pérez, Valero-López, Diaz-Diaz, Aladro, Brieva, Íñiguez, González-Suárez, Rodríguez de Antonio, García-Domínguez, Sabin, Llufriu, Masjuan, Costa-Frossard and Villar.

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EM received research grants, travel support or honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, and Sanofi-Genzyme; JK received speaker fees, research support, travel support, and/or served on advisory boards by ECTRIMS, Swiss MS Society, Swiss National Research Foundation (320030_189140/1), University of Basel, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi; VM-L received grants and consulting or speaking fees from Almirall, Biogen, Celgene, Genzyme, Merck, Novartis, Roche and Teva; JM-L has received grants and consulting or speaking fees from Almirall, Biogen, Bristol-Myers-Squibb, Genzyme, Merck, Novartis, Roche and Teva; GI has received consultancy/advice and Conference- travel support from Bayer, Novartis, Sanofi, Merck Serono, Roche, Actelion Celgene and Teva; CO-G has received speaker and consulting fees from Biogen, Celgene, Merck KGaA (Darmstadt, Germany), Novartis, Roche, Sanofi Genzyme and Teva; FG-G has received funding for research grants, travel support and honoraria for speaking engagements from: Bayer, Biogen, Roche, Merck, Novartis, Almirall, Teva and Genzyme-Sanofi; SS received research grants, travel support, or honoraria for speaking engagements from Almirall, Bayer, Biogen, Merck, Mylan, Novartis, Roche, Sanofi-Genzyme and Teva; AS reports compensation for consulting services and speaker honoraria from Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd, Novartis, Roche, and Alexion; YB received speaking honoraria from Biogen, Novartis and Genzyme; LB received funding for research projects or in the form of conference fees, mentoring, and assistance for conference attendance from: Bayer, Biogen, Roche, Merk, Novartis, Almirall, Celgen and Sanofi; IG-S received research grants, travel support and honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, TEVA and Alexion; LR received travel support, and honoraria for speaking engagements from Biogen, Merck, Roche and Sanofi-Genzyme; JS received funding for research projects and conference fees, mentoring, and assistance for conference attendance from: Teva, Merck, Biogen, Roche, Novartis, and Sanofi; SL received compensation for consulting services and speaking honoraria from Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd, Novartis and Roche; LC-F received speaker fees, travel support, and/or served on advisory boards by Biogen, Sanofi, Merck, Bayer, Novartis, Roche, Teva, Celgene, Ipsen, Biopas, Almirall; LV received research grants, travel support or honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Bristol-Myers. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.