FP.20 Serum metabolomics differentiates treatment response of myasthenia gravis clinical outcome measures

Abstract

The myasthenia gravis (MG) Activities of Daily Living (MG-ADL) and Quantitative MG (QMG) score QMG have been used as primary outcome measures in phase 3 clinical trials of therapeutics of MG. The MG-ADL is a patient-reported outcome measure of performance of common activities over a one to two-week period prior to assessment, while the QMG is a quantitated examination performed at one time by a trained examiner. We were interested if there was a difference in the biological signature of these measures. Using sera obtained at study entry to the thymectomy clinical trial (MGTX), an NIH-sponsored randomized, controlled study of thymectomy plus prednisone versus prednisone alone, we applied ultra-performance liquid chromatography coupled with electro-spray quadrupole time of flight mass spectrometry to obtain comparative serum metabolomic and lipidomic profiles at study entry to correlate with treatment response using the MG-ADL and QMG at 6 months. Principal component analysis, hierarchical clustering and pathway analysis were used to evaluate the profiles. There was limited overlap between the metabolomic and lipidomic profiles related to improvement in MG-ADL and QMG. Increased levels of phospholipids were associated with treatment response as assessed by QMG but not observed in the MG-ADL analysis. Pathway analysis also associated QMG change with alterations of lipid metabolism, while amino acid and glucose metabolism pathways were associated with MG-ADL improvement. The results indicate fundamentally different biological underpinnings of the outcome measures in common use in MG clinical trials and supports the common dissociation of patient and physician observation what is means to be better reflected is serum metabolites.