Importance:Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology. Objective:To identify CSF biological measures associated with progressive MS pathobiology. Design, Setting, and Participants:This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). Exposures:Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. Main Outcomes and Measures:Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]). Results:The test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = -0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = -0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). Conclusions and Relevance:In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20 dim CD8 + T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20 dim CD8 + T cells had a greater contribution to treatment-associated changes in the CD8 + T cell pool than was the case for CD4 + T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20 dim CD8 + T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19 + CD24 high CD38 high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20 dim CD8 + T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8 + T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

To assess longitudinal changes in B cells, T cells, neurofilament light (NfL) and soluble inflammatory markers in patients with primary progressive (PPMS) and relapsing (RMS) multiple sclerosis following ocrelizumab (OCR) treatment.

Objective: To provide interim analysis (IA) results from the relapsing multiple sclerosis (RMS) cohort of OBOE (Ocrelizumab Biomarker Outcome Evaluation; NCT02688985), a cerebrospinal fluid (CSF) and blood biomarker study. Background: Serum and CSF levels of neurofilament light chain (NfL) and CSF lymphocyte numbers are emerging biomarkers of axonal damage and inflammation, respectively. Responses of these biomarkers to ocrelizumab (OCR) may improve the understanding of MS pathophysiology and therapeutic mechanism of action. Design/Methods: Patients with RMS received OCR 600-mg infusions every 24 weeks. CSF samples were obtained by lumbar puncture (LP) before OCR and at 12, 24 or 52 weeks after initial OCR treatment. Patients in a nonrandomized RMS reference arm underwent two LPs 12 weeks apart prior to initiation of OCR. The primary endpoint is change in CSF NfL levels and lymphocyte numbers between pre- and post-treatment time points. All enrolled patients (n=100) are included in this IA. Results: Pretreatment CSF and serum NfL levels correlated strongly (r=0.78; p Conclusions: In RMS patients, ocrelizumab significantly decreased CSF/serum NfL and CSF B cells, suggesting that treatment reduces ongoing axonal injury and compartmentalized CNS inflammation. CSF B cells were almost completely depleted in most patients at Weeks 12, 24 and 52, whereas CSF T cells were moderately reduced in many but not all patients. Disclosure: Dr. Cross has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Celgene, EMD Serono, Genzyme, Genentech, Novartis. Dr. Cross has received research support from Genentech. Dr. Bennett has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Clene Nanomedicine, EMD Serono, Equillium Inc, Frequency Therapeutics, and Viela Bio. Dr. Bennett has received research support from EMD Serono. Dr. Von Budingen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche Ltd. Dr. Carruthers has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche, EMD Serono, Sanofi, Biogen, Novartis, and Teva. Dr. Carruthers has received research support from Teva Innovation Canada, Roche Canada. Dr. Edwards has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Genzyme, EMD Serono. Dr. Edwards has received research support from Biogen, Eli Lilly, Genentech, Genzyme/Sanofi, Hoffmann-La Roche, and Novartis. Dr. Fallis has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with EMD Serono. Dr. Fiore has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Gelfand has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Medimmune, Quest Diagnostics, and government and commercial entities for medical legal consulting. Dr. Gelfand has received personal compensation in an editorial capacity for Dynamed. Dr. Gelfand has received research support from Genentech and MedDay. Dr. Giacomini has nothing to disclose. Dr. Greenberg has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis, Alexion, EMD Serono. Dr. Greenberg has received research support from Chugai, Medimmune, Genentech, MedDay, PCORI, NIH, NMSS and Guthy Jackson Charitable Foundation for NMO. Dr. Hafler has nothing to disclose. Dr. Harp has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech Inc. Dr. Assman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Herman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech, Inc. Dr. Ionete has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sanofi. Dr. Ionete has received research support from Biogen, Roche, and Sanofi. Dr. Kaunzner has nothing to disclose. Dr. Lock has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen and Sanofi Genzyme. Dr. Ma has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech, Inc. Dr. Musch has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Pardo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Bayer, Biogen, EMD Serono, Genentech, Novartis, Sanofi, and Teva. Dr. Piehl has nothing to disclose. Dr. Weber has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen-Idec, Merck Serono, Novartis, Roche, TEVA, Bayer and Genzyme. Dr. Weber has received research support from Deutsche Forschungsgemeinschaft, Novartis, TEVA, Biogen-Idec, Roche, Merck and the ProFutura Program of the Universitatsmedizin Gottingen. Dr. Ziemssen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Bayer Healthcare, Biogen Idec, Novartis, Merck Serono, Teva, Genzyme, Synthon, Merck Sharp & Dohme, GlaxoSmithKline, Sanofi, and Almirall. Dr. Ziemssen has received research support from Bayer Healthcare, Biogen, Genzyme, Novartis, Teva, and Sanofi. Dr. Bar-Or has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Atara Biotherapeutics, Biogen, Celgene/Receptos, Genentech/Roche, GlaxoSmithKline, Medimmune, Merck/EMD Serono, Novartis, Sanofi-Genzyme. Dr. Bar-Or has received research support from Atara Biotherapeutics, Biogen, Celgene/Receptos, Genentech/Roche, GlaxoSmithKline, Medimmune, Merck/EMD Serono, Novartis, Sanofi-Genzyme.

Fatigue and cognitive impairment are debilitating features of multiple sclerosis (MS). ENER-G was a 12-month, open-label, multicenter, single-arm observational study designed to evaluate changes in fatigue and cognition in MS patients treated with natalizumab. Adults with relapsing MS and initiating natalizumab were enrolled. The primary endpoint was change in Visual Analog Scale for Fatigue (VAS-F) score over 12 weeks. Changes in Modified Fatigue Impact Scale (MFIS) score, Fatigue Severity Scale (FSS) score, and cognitive performance, using Automated Neuropsychological Assessment Metrics (ANAM), were also assessed. Patients (N = 89) had a mean age of 41 years and a median Expanded Disability Status Scale score of 3.0, and 83% had used at least two prior MS therapies. Significant improvements were observed and maintained at 12 weeks in VAS-F (mean ± SD baseline score, 77.7 ± 10.2; mean ± SD change, -14.9 ± 17.1; P < .0001), MFIS (mean baseline score, 59.1 ± 12.2; mean change, -7.4 ± 11.8; P < .0001), and FSS (median baseline score, 6.3 [range, 3.9-7.0]; median change, -0.4 [range, -2.9-1.4]; P < .0001). Cognitive performance remained stable or improved (depending on the ANAM measure). Thus significant improvements in fatigue were maintained over time, and cognitive performance improved or remained stable up to 48 weeks after initiation of natalizumab in MS patients with some degree of fatigue.

Annals of the New York Academy of SciencesVolume 436, Issue 1 p. 373-381 The Use of Cyclophosphamide in the Treatment of Multiple Sclerosisa HOWARD L. WEINER, HOWARD L. WEINER Multiple Sclerosis Clinical and Research Unit Division of Neurology Department of Medicine Brigham and Women's Hospital Boston, Massachusetts 02115 Harvard Medical School Boston, Massachusetts 02115Search for more papers by this authorSTEPHEN L. HAUSER, STEPHEN L. HAUSER Multiple Sclerosis Clinical and Research Unit Division of Neurology Department of Medicine Brigham and Women's Hospital Boston, Massachusetts 02115 Harvard Medical School Boston, Massachusetts 02115Search for more papers by this authorDAVID A. HAFLER, DAVID A. HAFLER Multiple Sclerosis Clinical and Research Unit Division of Neurology Department of Medicine Brigham and Women's Hospital Boston, Massachusetts 02115 Harvard Medical School Boston, Massachusetts 02115Search for more papers by this authorROBERT J. FALLIS, ROBERT J. FALLIS Multiple Sclerosis Clinical and Research Unit Division of Neurology Department of Medicine Brigham and Women's Hospital Boston, Massachusetts 02115 Harvard Medical School Boston, Massachusetts 02115Search for more papers by this authorJAMES R. LEHRICH, JAMES R. LEHRICH Department of Neurology Massachusetts General Hospital Boston. Massachusetts 02114 Harvard Medical School Boston, Massachusetts 02115Search for more papers by this authorDAVID M. DAWSON, DAVID M. DAWSON Multiple Sclerosis Clinical and Research Unit Division of Neurology Department of Medicine Brigham and Women's Hospital Boston, Massachusetts 02115 Harvard Medical School Boston, Massachusetts 02115Search for more papers by this author HOWARD L. WEINER, HOWARD L. WEINER Multiple Sclerosis Clinical and Research Unit Division of Neurology Department of Medicine Brigham and Women's Hospital Boston, Massachusetts 02115 Harvard Medical School Boston, Massachusetts 02115Search for more papers by this authorSTEPHEN L. HAUSER, STEPHEN L. HAUSER Multiple Sclerosis Clinical and Research Unit Division of Neurology Department of Medicine Brigham and Women's Hospital Boston, Massachusetts 02115 Harvard Medical School Boston, Massachusetts 02115Search for more papers by this authorDAVID A. HAFLER, DAVID A. HAFLER Multiple Sclerosis Clinical and Research Unit Division of Neurology Department of Medicine Brigham and Women's Hospital Boston, Massachusetts 02115 Harvard Medical School Boston, Massachusetts 02115Search for more papers by this authorROBERT J. FALLIS, ROBERT J. FALLIS Multiple Sclerosis Clinical and Research Unit Division of Neurology Department of Medicine Brigham and Women's Hospital Boston, Massachusetts 02115 Harvard Medical School Boston, Massachusetts 02115Search for more papers by this authorJAMES R. LEHRICH, JAMES R. LEHRICH Department of Neurology Massachusetts General Hospital Boston. Massachusetts 02114 Harvard Medical School Boston, Massachusetts 02115Search for more papers by this authorDAVID M. DAWSON, DAVID M. DAWSON Multiple Sclerosis Clinical and Research Unit Division of Neurology Department of Medicine Brigham and Women's Hospital Boston, Massachusetts 02115 Harvard Medical School Boston, Massachusetts 02115Search for more papers by this author First published: December 1984 https://doi.org/10.1111/j.1749-6632.1984.tb14808.xCitations: 17 a This work was supported by NIH grant no. NS-17182. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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