Saurabh Gawde1, Agnieshka Agasing1, Neal Bhatt2, Mackenzie Toliver2, Gaurav Kumar2, Kaylea Massey2, Andrew Nguyen2, Yang Mao-Draayer3, Susan Macwana2, Wade DeJager2, Joel M Guthridge2, Gabriel Pardo4, Jeffrey Dunn5, Robert C Axtell6. 1. Department of Arthritis and Clinical Immunology Research, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. 2. Department of Arthritis and Clinical Immunology Research, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. 3. Department of Neurology, Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI, USA. 4. Department of Arthritis and Clinical Immunology Research, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Multiple Sclerosis Center of Excellence, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. 5. Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA. 6. Department of Arthritis and Clinical Immunology Research, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. Electronic address: bob-axtell@omrf.org.
Abstract
BACKGROUND: For relapsing-remitting multiple sclerosis (RRMS), there is a need for biomarker development beyond clinical manifestations and MRI. Soluble neurofilament light chain (sNfL) has emerged as a biomarker for inflammatory activity in RRMS. However, there are limitations to the accuracy of sNfL in identifying relapses. Here, we sought to identify a panel of biomarkers that would increase the precision of distinguishing patients in relapse compared to sNfL alone. METHODS: We used a multiplex approach to measure levels of 724 blood proteins in two distinct RRMS cohorts. Multiple t-tests with covariate correction determined biomarkers that were differentially regulated in relapse and remission. Logistic regression models determined the accuracy of biomarkers to distinguish relapses from remission. RESULTS: The discovery cohort identified 37 proteins differentially abundant in active RRMS relapse compared to remission. The verification cohort confirmed four proteins, including sNfL, were altered in active RRMS relapse compared to remission. Logistic regression showed that the 4-protein panel identified active relapse with higher accuracy (AUC = 0.87) than sNfL alone (AUC = 0.69). CONCLUSION: Our studies confirmed that sNfL is elevated during relapses in RRMS patients. Furthermore, we identified three other blood proteins, uPA, hK8 and DSG3 that were altered during relapse. Together, these four biomarkers could be used to monitor disease activity in RRMS patients.
BACKGROUND: For relapsing-remitting multiple sclerosis (RRMS), there is a need for biomarker development beyond clinical manifestations and MRI. Soluble neurofilament light chain (sNfL) has emerged as a biomarker for inflammatory activity in RRMS. However, there are limitations to the accuracy of sNfL in identifying relapses. Here, we sought to identify a panel of biomarkers that would increase the precision of distinguishing patients in relapse compared to sNfL alone. METHODS: We used a multiplex approach to measure levels of 724 blood proteins in two distinct RRMS cohorts. Multiple t-tests with covariate correction determined biomarkers that were differentially regulated in relapse and remission. Logistic regression models determined the accuracy of biomarkers to distinguish relapses from remission. RESULTS: The discovery cohort identified 37 proteins differentially abundant in active RRMS relapse compared to remission. The verification cohort confirmed four proteins, including sNfL, were altered in active RRMS relapse compared to remission. Logistic regression showed that the 4-protein panel identified active relapse with higher accuracy (AUC = 0.87) than sNfL alone (AUC = 0.69). CONCLUSION: Our studies confirmed that sNfL is elevated during relapses in RRMS patients. Furthermore, we identified three other blood proteins, uPA, hK8 and DSG3 that were altered during relapse. Together, these four biomarkers could be used to monitor disease activity in RRMS patients.
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