Abstract Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. Here, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster of PwMS that share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active prodromal period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid (CSF) and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically- or radiologically-isolated neuroinflammatory syndromes.
This Viewpoint describes the benefits and limitations of using neurofilament light chain (NfL) as a marker of real-time disease activity and treatment response in multiple sclerosis.
To compare how serum glial fibrillary acidic protein (sGFAP) and neurofilament light chain (sNfL) correlate with progression and acute inflammation in multiple sclerosis (MS).
Background:
There are insufficient diagnostic tools to anticipate 'pure progression' and acute inflammation in MS.
Design/Methods:
sGFAP and sNfL were measured using Simoa assays in three cohorts of patients of the Swiss MS Cohort: 1) worsening progressive MS (wPMS; 184 samples (s)/18 patients (p), median follow-up (FU): 6.5 years (y), median EDSS baseline (BL)/last visit 4.0/6.0); 2) clinically stable MS (stMS; 169s/19p, 7.1 y, EDSS 3.0/2.5) (both relapse-free during FU); 3) Relapsing MS (132s/66p) during a) acute disease activity (relapse/contrast enhancing lesions); 66s) and b) stable phase (66s); and healthy controls (HC; 485s/259p; BL and 1y FU). Multivariable mixed models were applied to longitudinally compare log-transformed sGFAP/sNfL between groups 1) versus 2); 3a) versus 3b); and adjusted mixed/Cox regression models for the association between BL sGFAP/sNfL levels and brain volume loss (BVL) and time to confirmed disability worsening (CDW) in groups 1) and 2).
Results:
sGFAP increased in HC with age (1.5%/y, p<0.001), decreased with body mass index (−1.1%/BMI unit, p=0.015) and was 15% higher in women than men (p=0.004). wPMS patients showed 57% higher sGFAP levels versus stMS (p=0.006) and remained 51% higher after sNfL adjustment in the model (p=0.010). In contrast, the 25% increase of sNfL in wPMS versus stMS (p=0.046) disappeared after sGFAP adjustment. Acute disease activity had no effect on sGFAP, while it increased sNfL by 53% (p<0.001). Higher sGFAP at BL was associated with accelerated gray matter BVL (per doubling (pd): 0.24%, p<0.0001), but not white matter (p=0.48). sGFAP, but not sNfL levels were associated with shorter time to CDW (HR pd: 3.63, p=0.006; HR pd: 1.90, p=0.112).
Conclusions:
sGFAP may be a more specific biomarker for 'pure progression' than sNfL. Disclosure: Miss Meier has nothing to disclose. Pascal Benkert has nothing to disclose. Aleksandra Maleska Maceski has nothing to disclose. Sabine Schaedelin has nothing to disclose. The institution of Dr. Oechtering has received research support from Swiss MS Society. Dr. Melie-Garcia has nothing to disclose. Dr. Cagol has nothing to disclose. Mr. Barakovic has nothing to disclose. Dr. Galbusera has nothing to disclose. Lutz Achtnichts has nothing to disclose. Dr. LaLive has nothing to disclose. Claire Bridel has nothing to disclose. Stefanie Mueller-Schunk has nothing to disclose. Caroline Pot has nothing to disclose. The institution of Anke Salmen has received research support from Baasch Medicus Foundation. The institution of Anke Salmen has received research support from Swiss MS Society. The institution of Anke Salmen has received research support from Medical Faculty of the University of Bern. Anke Salmen has received personal compensation in the range of $500-$4,999 for serving as a speaker with Bristol Myers Squibb, CSL Behring, Novartis, Roche. The institution of Dr. Disanto has received research support from Swiss MS Sociery. The institution of Dr. Zecca has received research support from Ente Ospedaliero Cantonale. The institution of Dr. Abdelhak has received research support from German Multiple Sclerosis Society. Dr. Barro has nothing to disclose. Dr. Thebault has nothing to disclose. Dr. D'Souza has nothing to disclose. An immediate family member of Tobias Derfuss has received personal compensation for serving as an employee of Novartis. The institution of Tobias Derfuss has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. The institution of Tobias Derfuss has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. The institution of Tobias Derfuss has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merck. The institution of Tobias Derfuss has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. The institution of Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Celgene. The institution of Tobias Derfuss has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for GeNeuro. Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for MedDay. Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Actelion. Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Merck. Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Roche. An immediate family member of Tobias Derfuss has received stock or an ownership interest from Novartis. The institution of Tobias Derfuss has received research support from Roche. The institution of Tobias Derfuss has received research support from Biogen. Dr. Orleth has nothing to disclose. Michael Khalil has nothing to disclose. Dr. Yaldizli has nothing to disclose. Dr. Hermesdorf has nothing to disclose. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bristol Myers Squibb. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Immunovant. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Johnson&Johnson / Janssen. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB. Dr. Wiendl has received personal compensation in the range of $0-$499 for serving as a Consultant for Idorsia. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Actelion. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Argenx. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gossamer Bio. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Immunic. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merck. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NexGen. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for PSI CRO. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Worldwide Clinical Trials. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BD. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck Serono. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Janssen. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bristol Myers Squibb. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sandoz. The institution of Dr. Wiendl has received research support from Biogen. The institution of Dr. Wiendl has received research support from Roche. The institution of Dr. Wiendl has received research support from Deutsche Forschungsgemeinschaft. The institution of Dr. Wiendl has received research support from European Union. The institution of Dr. Wiendl has received research support from Alexion. The institution of Dr. Wiendl has received research support from Argenx. The institution of Dr. Wiendl has received research support from CSL Behring. The institution of Dr. Wiendl has received research support from Merck. The institution of Dr. Wiendl has received research support from UCB. Dr. Wiendl has received publishing royalties from a publication relating to health care. Dr. Wiendl has received publishing royalties from a publication relating to health care. Dr. Piehl has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Parexel/Chugai. The institution of Dr. Piehl has received research support from UCB. The institution of Dr. Piehl has received research support from Merck KGaA. Dr. Piehl has received personal compensation in the range of $10,000-$49,999 for serving as a member scientific advisory board with Swedish Medical products Agency. The institution of Urs Fischer has received research support from Medtronic. The institution of Urs Fischer has received research support from Medtronic. The institution of Dr. Kappos has received research support from Bayer. The institution of Dr. Kappos has received research support from Biogen. The institution of Dr. Kappos has received research support from Genentech. The institution of Dr. Kappos has received research support from Genzyme. The institution of Dr. Kappos has received research support from Janssen. The institution of Dr. Kappos has received research support from Merck Serono. The institution of Dr. Kappos has received research support from Minoryx. The institution of Dr. Kappos has received research support from Novartis. The institution of Dr. Kappos has received research support from Roche. The institution of Dr. Kappos has received research support from Sanofi. The institution of Dr. Kappos has received research support from Santhera. The institution of Dr. Kappos has received research support from Swiss MS Society, Swiss National Research Foundation, European Union, Roche Research Foundation, Innosuisse. The institution of Dr. Kappos has received research support from Shionogi. The institution of Dr. Kappos has received research support from Japan Tobacco. The institution of Dr. Kappos has received research support from Auriga Vision AG. The institution of Dr. Kappos has received research support from EMD Serono. The institution of Dr. Kappos has received research support from Glaxo Smith Kline. The institution of Dr. Kappos has received research support from Wellmera AG. The institution of Dr. Kappos has received research support from Eli Lilly (Suisse) SA. The institution of Dr. Kappos has received research support from Bristol Myers Squibb. The institution of Dr. Kappos has received research support from Celltrion Inc. Dr. Kappos has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Gobbi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie, Almirall, Biogen Idec, Celgene, Sanofi, Merck, Novartis, Teva Pharma, Roche.. Dr. Gobbi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie, Almirall, Biogen Idec, Celgene, Sanofi, Merck, Novartis, Teva Pharma, Roche.. Dr. Granziera has nothing to disclose. Dr. Leppert has received personal compensation for serving as an employee of GeNeuro. Dr. Leppert has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Leppert has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Leppert has received personal compensation in the range of $0-$499 for serving as a Consultant for Orion. Dr. Leppert has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Leppert has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Quanterix. Dr. Leppert has received stock or an ownership interest from Novartis. Dr. Willemse has nothing to disclose. Dr. Kuhle has nothing to disclose.
Abstract Background Proper identification of disability accumulation in the routine clinical care of progressive multiple sclerosis (PMS) patients is usually a challenging task. Patient-reported outcome measurements (PROMs) can provide a practical, cost-efficient, and remotely accessible tool to assess disease progression. Methods EmBioProMS is a prospective, multicentric cohort, conducted in 7 specialized MS centers in Germany. PROMs were evaluated at inclusion and compared between patients with retrospective evidence of disease progression in the last two years and those with stable disease. Patients with either primary or secondary progressive MS according to the McDonald criteria 2017 were included in the analysis, while patients with incomplete PROMs scores, MS relapses, other neurological or systemic inflammatory diseases were excluded. The disease progression was assessed using a combined outcome parameter, including EDSS score, timed 25-foot walk test, and nine-hole-peg test. Results 185 patients were included in the final analysis (SPMS, n=77; PPMS, n=108). The median age and disease duration were 55 years and 13 years, respectively. Disease progression was diagnosed in 114 of 185 patients (61.6%). BDI-II, MSIS-29, and FSMC scores were worse in patients with evidence of disease progression in the last two years. Patients with any of the included PROMs above the 90th percentile had an odds ratio of 3.8 (95% confidence interval: 1.4–10.6, P=0.01) for having progression in the last two years in a binomial regression model adjusted for age, sex, disease duration, treatment status, center effect, and Expanded Disability Status Scale (EDSS). Similar results were observed in patients with PROM scores in the 80th and 70th percentile (OR: 2.9 and 3.7, P=0.015 and 0.003, respectively). Conclusion PROMs can be a simple and effective way to detect disability worsening in a chronic neurological disease like PMS and, therefore, substantially contribute to better classification and prognostication of the disease course through objective and structural patient-doctor communication. Trial Registration German Clinical Trials Register (Deutsches Register Klinischer Studien - DRKS), DRKS00020132
Aim of work:To assess the effect of fasting for a whole month during Ramadan on the fetal Doppler indices and amniotic fluid index. Patients and Methods:The study involved 240 healthy women in the third trimester of a normal singleton pregnancy.The umbilical artery resistance index (RI) and middle cerebral artery (MCA) pulsatility index (PI) and the amniotic fluid index were measured at the beginning of Ramadan and at the end of the month.Of the included women, 157 (65.4%) chose to fast (Group 1) and 83 (34.6%) were not fasting (Group 2).Results: On reassessment, 9 participants were lost to follow up, 2 women developed hypertension and another woman had preterm delivery.Thus, results at the end of Ramadan were presented for 228 women; 152 in the fasting and 76 in the non-fasting group.On initial assessment, there was no significant difference between fasting and non-fasting women regarding umbilical artery RI (p = 0.645), MCA PI (p = 0.581) and AMF (p = 0.070).During re-assessment at the end of Ramadan, there was no significant difference between the two groups regarding umbilical artery RI (p = 0.519), MCA PI (p = 0.383) and AMF (p = 0.339).At the end of Ramadan, there was a statistically significant decrease of Doppler indices and AFI.However, all values were within the clinically accepted range.Conclusion: Maternal fasting during Ramadan does not adversely affects fetal condition based on finding of normal Doppler indices and amniotic fluid index, provided woman is young and healthy.
Background We aimed to investigate the potential of serum biomarker levels to predict disability progression in a multicentric real-world cohort of patients with primary progressive multiple sclerosis (PPMS). Methods A total of 141 patients with PPMS from 18 European MS centres were included. Disability progression was investigated using change in Expanded Disability Status Scale (EDSS) score over three time intervals: baseline to 2 years, 6 years and to the last follow-up. Serum levels of neurofilament light chain (sNfL), glial fibrillar acidic protein (sGFAP) and chitinase 3-like 1 (sCHI3L1) were measured using single-molecule array assays at baseline. Correlations between biomarker levels, and between biomarkers and age were quantified using Spearman’s r. Univariable and multivariable linear models were performed to assess associations between biomarker levels and EDSS change over the different time periods. Results Median (IQR) age of patients was 52.9 (46.4–58.5) years, and 58 (41.1%) were men. Median follow-up time was 9.1 (7.0–12.6) years. Only 8 (5.7%) patients received treatment during follow-up. sNfL and sGFAP levels were moderately correlated (r=0.43) and both weakly correlated with sCHI3L1 levels (r=0.19 and r=0.17, respectively). In multivariable analyses, levels of the three biomarkers were associated with EDSS changes across all time periods. However, when analysis was restricted to non-inflammatory patients according to clinical and radiological parameters (n=64), only sCHI3L1 levels remained associated with future EDSS change. Conclusions Levels of sNfL, sGFAP and sCHI3L1 are prognostic biomarkers associated with disability progression in patients with PPMS, being CHI3L1 findings less dependent on the inflammatory component associated with disease progression.
Markers predicting the course of patients with clinically isolated syndrome (CIS) toward multiple sclerosis (MS) are urgently needed. We evaluated the predictive values of intrathecal immunoglobulin (Ig) G and IgM production with different methods for conversion to definite MS according to revised McDonald 2010 criteria in a cohort of 126 CIS patients. Intrathecal IgM production showed the highest likelihood ratio for the conversion of CIS patients to definite MS at 6.3, whereas it was 1.4 for oligoclonal IgG bands. We conclude that the determination of intrathecal IgM is a valuable tool to predict the disease course of patients with CIS. Ann Neurol 2018;83:1032–1036
The timing of neurodegeneration in multiple sclerosis (MS) remains unclear. It is critical to understand the dynamics of neuroaxonal loss if we hope to prevent or forestall permanent disability in MS. We therefore used a deeply phenotyped longitudinal cohort to assess and compare rates of neurodegeneration in retina and brain throughout the MS disease course.
Methods
We analyzed 597 patients with MS who underwent longitudinal optical coherence tomography imaging annually for 4.5 ± 2.4 years and 432 patients who underwent longitudinal MRI scans for 10 ± 3.4 years, quantifying macular ganglion cell-inner plexiform layer (GCIPL) volume and cortical gray matter (CGM) volume. The association between the slope of decline in the anatomical structure and the age of entry in the cohort (categorized by the MRI cohort9s age quartiles) was assessed by hierarchical linear models.
Results
The rate of CGM volume loss declined with increasing age of study entry (1.3% per year atrophy for the age of entry in the cohort younger than 35 years; 1.1% for older than 35 years and younger than 41; 0.97% for older than 41 years and younger than 49; 0.9% for older than 49 years) while the rate of GCIPL thinning was highest in patients in the youngest quartile, fell by more than 50% in the following age quartile, and then stabilized (0.7% per year thinning for the age of entry in the cohort younger than 35 years; 0.29% for age older than 35 and younger than 41 years; 0.34% for older than 41 and younger than 49 years; 0.33% for age older than 49 years).
Discussion
An age-dependent reduction in retinal and cortical volume loss rates during relapsing-remitting MS suggests deceleration in neurodegeneration in the earlier period of disease and further indicates that the period of greatest adaptive immune–mediated inflammatory activity is also the period with the greatest neuroaxonal loss.
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