Abstract
Introduction
Myasthenia gravis (MG) is a chronic, potentially debilitating autoimmune disease characterized by weakness and rapid fatigue of the voluntary muscles that worsens on exertion. Left untreated, MG symptoms may cause significant morbidity or even death. To date, no robust biological marker is available to follow the course of the disease. Therefore, new diagnostic approaches and biological markers are essential not only for improved diagnosis of the disease but for improved outcomes.
Objectives
The present study applied a two-control, multi-label metabolomics profiling approach as a potential strategy for the identification of biomarkers unique to myasthenia gravis (MG).
Methods
Metabolic analyses using acid- and dansyl-labelled serum from seropositive MG (n = 46), rheumatoid arthritis (RA) (n = 23) and healthy controls (HC) (n = 49) were performed on samples from adult patients presenting to the University of Alberta Hospital neuromuscular and rheumatology clinics. Comparisons between patients with MG vs. HC, and RA vs. HC were made using univariate and multivariate statistics.
Results
Serum biomarker patterns were statistically significantly different between groups. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) models exhibited considerable distinction between all groups. Metabolites were then filtered to remove peak pairs common to both disease cohorts. Combined metabolite panels revealed clear separation between MG and HC for both library-matched (AUROC: 0.92 ± 0.03) and highest AUC patients (AUROC: 0.94 ± 0.05).
Conclusion
In patients presenting to the clinic with seropositive MG, metabolomic profiling is capable of distinguishing patients with disease from those without. These results provide an important first step towards a potential biomarker for improving MG identification.
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DB developed the concept and designed the experiment, acquired all blood samples but those from rheumatoid arthritis patients, conducted all databasing, bioinformatics analyses and metabolite-database matching. Further, DB prepared all charts, images and tables and wrote the paper. ZS provided project oversight as the clinical expert in myasthenia gravis. ZS also offered conceptual advice, supervised project analysis and edited the manuscript. LL developed the chemical labelling process and several chemometric analysis tools used in this study as well as the chemical identification libraries used in the positive identification of observed metabolites. LL provided oversight in the choice of chemical and statistical techniques used to characterize the metabolome. LL also offered conceptual advice, supervised project analysis and edited the manuscript. NW performed the sample preparation, chemical labelling and mass spectrometric analysis. WM provided the rheumatoid arthritis samples for the disease control cohort. All authors reviewed the manuscript.
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Blackmore, D., Siddiqi, Z., Li, L. et al. Beyond the antibodies: serum metabolomic profiling of myasthenia gravis. Metabolomics 15, 109 (2019). https://doi.org/10.1007/s11306-019-1571-9
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DOI: https://doi.org/10.1007/s11306-019-1571-9