Serum Metabolomic Response of Myasthenia Gravis Patients to Chronic Prednisone Treatment

Abstract

Prednisone is often used for the treatment of autoimmune and inflammatory diseases but they suffer from variable therapeutic responses and significant adverse effects. Serum biological markers that are modulated by chronic corticosteroid use have not been identified. Myasthenia gravis is an autoimmune neuromuscular disorder caused by antibodies directed against proteins present at the post-synaptic surface of neuromuscular junction resulting in weakness. The patients with myasthenia gravis are primarily treated with prednisone. We analyzed the metabolomic profile of serum collected from patients prior to and after 12 weeks of prednisone treatment during a clinical trial. Our aim was to identify metabolites that may be treatment responsive and be evaluated in future studies as potential biomarkers of efficacy or adverse effects. Ultra-performance liquid chromatography coupled with electro-spray quadrupole time of flight mass spectrometry was used to obtain comparative metabolomic and lipidomic profile. Untargeted metabolic profiling of serum showed a clear distinction between pre- and post- treatment groups. Chronic prednisone treatment caused upregulation of membrane associated glycerophospholipids: phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, 1, 2-diacyl-sn glycerol 3 phosphate and 1-Acyl-sn-glycero-3-phosphocholine. Arachidonic acid (AA) and AA derived pro-inflammatory eicosanoids such as 18-carboxy dinor leukotriene B4 and 15 hydroxyeicosatetraenoic acids were reduced. Perturbations in amino acid, carbohydrate, vitamin and lipid metabolism were observed. Chronic prednisone treatment caused increase in membrane associated glycerophospholipids, which may be associated with certain adverse effects. Decrease of AA and AA derived pro-inflammatory eicosanoids demonstrate that immunosuppression by corticosteroid is via suppression of pro-inflammatory pathways. The study identified metabolomic fingerprints that can now be validated as prednisone responsive biomarkers for the improvement in diagnostic accuracy and prediction of therapeutic outcome.

Patients with Treatment-Requiring Chronic Graft versus Host Disease after Allogeneic Stem Cell Transplantation Have Altered Metabolic Profiles due to the Disease and Immunosuppressive Therapy: Potential Implication for Biomarkers

“…Taken together these observations suggest that the increased levels of these overlapping metabolites in cGVHD patients are mainly due to the steroid treatment rather than the cGVHD. Our present results are consistent with previous studies of steroid-treated myasthenia gravis patients showing that steroids alter triglyceride/fatty acid metabolism ( 38 ). However, one cannot exclude the possibility that even these steroid-associated effects may be at least partly due to the more severe and thereby steroid-requiring cGVHD of these patients.…”

Unraveling the Role of Receptor for Advanced Glycation End Products (RAGE) and Its Ligands in Myasthenia Gravis

“…Phosphatidylserine, another RAGE ligand, is a component of the cell membrane that is involved in various signaling pathways implicated in apoptosis and inflammatory responses. A recent study that examined the serum metabolomic profile of MG patients before and after 12 weeks of prednisone treatment demonstrated that various membrane-associated glycerophospholipids, such as phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine, were upregulated upon chronic treatment with prednisone, whereas other proinflammatory metabolites were reduced, highlighting a significant prednisone-induced alteration in glycerophospholipid metabolism in these patients . Therefore, monitoring glycerophospholipid levels could represent a novel approach toward assessing treatment response to prednisone in MG patients.…”

Myasthenic ophthalmoparesis: Time To resolution after initiating immune therapies

“…Although the mechanisms of action of prednisone at the myasthenic EOM end plate is unknown, a study in 15 patients with MG assessing the metabolomic response in sera to treatment with low doses of prednisone (0.29 mg/kg/day) in the first 12 weeks showed an upregulation of membrane-associated glycerophospholipids and downregulation of proinflammatory pathways. 28 This is interesting because we have reported that the pathogenetic mechanisms underlying the ophthalmoplegic treatment-resistant MG subphenotype may, in part, be due to aberrant muscle end plate membrane repair and stability, and specifically gangliosphingolipid metabolism. 11,14 Our study has limitations.…”