NMR based Serum and Muscle Metabolomics for Diagnosis and Activity Assessment in Idiopathic Inflammatory Myopathies

Differentiating smouldering disease activity from weakness due to fatty replacement of atrophied muscle can often be a challenge in the Idiopathic Inflammatory Myositis (IIM). Conventional biomarkers such creatine kinase (CK) may be normal in the face of significant muscle wasting. Therefore, we aimed to identify the metabolic disturbances associated with IIM and tried to explore if these changes can aid in the assessment of disease activity as well. For this, metabolic profiles of sera (N=99) and muscle (N=21) from patients with IIM (ACR-EULAR criteria) were compared with healthy control (HC) samples (N=75 for serum and N=12 for muscle tissues) employing 800 MHz NMR (Nuclear Magnetic Resonance) Spectroscopy. Metabolic disparity between IIM and HC was established based on Partial Least Squares Discriminant Analysis (PLS-DA) and the discriminatory metabolites were identified based on variable importance in projection (VIP) statistics). The results revealed that the serum metabolomics profiles of IIM patients are distinctively different compared to HC, with a visible shift to anaerobic metabolism (as inferred from the increased circulatory levels of lactate and decreased glucose levels), oxidative defect (high Phenylalanine/tyrosine), decreased muscle mass (low serum creatinine), increased muscle catabolism (increased branched chain amino acids) and dyslipidemia (higher lipids, higher (very low density lipoprotein (VLDL)/ low density lipoprotein (LDL) ratio, lower Polyunsaturated fatty acid (PUFA)). The sera of active IIM patients were characterized by anerobic metabolism (low glucose), loss of muscle mass (low creatinine, amino acids) and oxidative defect (high Phenylalanine/tyrosine). Three metabolites (isopropanol, succinate and glycine) were distinctive in muscle tissue metabolomics. NMR based serum metabolic disparity was lacking between different clinical subsets of IIM. In conclusion, the NMR based serum metabolic profiling could (i) differentiate active from inactive myositis where conventional markers fail and (ii) aid in critical decisions of whether to continue immune-suppressants or not in the patient. Thus, we believe that eerum and muscle tissue metabolomics has the potential to distinguish (i) IIM from HC and (ii) active IIM from inactive IIM without alteration due to disease subtype.