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Serum proteomic, peptidomic and metabolomic profiles in myasthenia gravis patients during treatment with Qiangji Jianli Fang.

ABSTRACT: BACKGROUND:Qiangji Jianli Fang (QJF) has been used for treatment of myasthenia gravis (MG) in China. However, our understanding of the effects of QJF against MG at the molecular level is limited. This study aims to investigate the effects of QJF treatment of MG patients on the protein, peptide and metabolite levels in serum. METHODS:High-throughput proteomic, peptidomic and metabolomic techniques were applied to investigate serum samples from 21 healthy individuals and 47 MG patients before and after QJF treatment via two-dimensional gel electrophoresis, matrix-assisted laser desorption/ionization time of flight mass spectrometry and liquid chromatography Fourier transform mass spectrometry, respectively. RESULTS:After QJF treatment, the expression levels of peptides m/z 1865.019, 2021.128 and 1211.668 of complement C3f increased (P?=?0.004, P?=?0.001 and P?=?0.043, respectively), while that of peptide m/z 1739.931 of component C4b decreased (P?=?0.043), in the serum of MG patients. The levels of ?-aminobutyric acid (P?=?0.000) and coenzyme Q4 (P?=?0.000) resumed their normal states. CONCLUSION:QJF could inhibit the activity of the complement system and restore the normal levels of metabolites.

SUBMITTER: Wang C

PROVIDER: S-EPMC3464942 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Serum proteomic, peptidomic and metabolomic profiles in myasthenia gravis patients during treatment with Qiangji Jianli Fang.

Wang Chunmei C Lu Yonghai Y Chen Zhixi Z Liu Xiaobin X Lin Huangquan H Zhao Hui H Chen Jinyan J Kwan Yiuwa Y Ngai Saiming S

Chinese medicine 20120728 1

<h4>Background</h4>Qiangji Jianli Fang (QJF) has been used for treatment of myasthenia gravis (MG) in China. However, our understanding of the effects of QJF against MG at the molecular level is limited. This study aims to investigate the effects of QJF treatment of MG patients on the protein, peptide and metabolite levels in serum.<h4>Methods</h4>High-throughput proteomic, peptidomic and metabolomic techniques were applied to investigate serum samples from 21 healthy individuals and 47 MG patie ...[more]

PMID: 22838635

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Project description: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.

Project description:ObjectiveHigh-dose prednisone use, lasting several months or longer, is the primary initial therapy for myasthenia gravis (MG). Upwards of a third of patients do not respond to treatment. Currently no biomarkers can predict clinical responsiveness to corticosteroid treatment. We conducted a discovery-based study to identify treatment responsive biomarkers in MG 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.MethodsWe 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 at 6 months. Treatment response was assessed using validated outcome measures of minimal manifestation status (MMS), MG-Activities of Daily Living (MG-ADL), Quantitative MG (QMG) score, or a strictly defined composite measure of response.ResultsIncreased serum levels of phospholipids were associated with treatment response as assessed by QMG, MMS, and the Responders classification, but all measures showed limited overlap in metabolomic profiles, in particular the MG-ADL. A panel including histidine, free fatty acid (13:0), γ-cholestenol and guanosine was highly predictive of the strictly defined treatment response measure. The AUC in Responders' prediction for these markers was 0.90 irrespective of gender, age, thymectomy or baseline prednisone use. Pathway analysis suggests that xenobiotic metabolism could play a major role in treatment resistance. There was no association with outcome and gender, age, thymectomy or baseline prednisone use.InterpretationWe have defined a metabolomic and lipidomic profile that can now undergo validation as a treatment predictive marker for MG patients undergoing corticosteroid therapy. Metabolomic profiles of outcome measures had limited overlap consistent with their assessing distinct aspects of treatment response and supporting unique biological underpinning for each outcome measure. Interindividual variation in prednisone metabolism may be a determinate of how well patients respond to treatment.

Project description:ImportanceUse of biologic agents in generalized myasthenia gravis is generally limited to therapy-refractory cases; benefit in new-onset disease is unknown.ObjectiveTo assess rituximab in refractory and new-onset generalized myasthenia gravis and rituximab vs conventional immunotherapy in new-onset disease.Design, setting, and participantsA retrospective cohort study with prospectively collected data was conducted on a county-based community sample at Karolinska University Hospital, Stockholm, Sweden. Participants included 72 patients with myasthenia gravis, excluding those displaying muscle-specific tyrosine kinase antibodies, initiating rituximab treatment from January 1, 2010, to December 31, 2018, and patients with new-onset disease initiating conventional immunotherapy from January 1, 2003, to December 31, 2012, with 12 months or more of observation time. The present study was conducted from March 1, 2019, to January 31, 2020.ExposuresTreatment with low-dose rituximab (most often 500 mg every 6 months) or conventional immunosuppressants.Main outcomes and measuresTime to remission (main outcome) as well as use of rescue therapies or additional immunotherapies and time in remission (secondary outcomes).ResultsOf the 72 patients included, 31 patients (43%) were women; mean (SD) age at treatment start was 60 (18) years. Twenty-four patients had received rituximab within 12 months of disease onset and 48 received rituximab at a later time, 34 of whom had therapy-refractory disease. A total of 26 patients (3 [12%] women; mean [SD] age, 68 [11] years at treatment start) received conventional immunosuppressant therapy. Median time to remission was shorter for new-onset vs refractory disease (7 vs 16 months: hazard ratio [HR], 2.53; 95% CI, 1.26-5.07; P = .009 after adjustment for age, sex, and disease severity) and for rituximab vs conventional immunosuppressant therapies (7 vs 11 months: HR, 2.97; 95% CI, 1.43-6.18; P = .004 after adjustment). In addition, fewer rescue therapy episodes during the first 24 months were required (mean [SD], 0.38 [1.10] vs 1.31 [1.59] times; mean difference, -1.26; 95% CI, -1.97 to -0.56; P < .001 after adjustment), and a larger proportion of patients had minimal or no need of additional immunotherapies (70% vs 35%; OR, 5.47; 95% CI, 1.40-21.43; P = .02 after adjustment). Rates of treatment discontinuation due to adverse events were lower with rituximab compared with conventional therapies (3% vs 46%; P < .001 after adjustment).Conclusions and relevanceClinical outcomes with rituximab appeared to be more favorable in new-onset generalized myasthenia gravis, and rituximab also appeared to perform better than conventional immunosuppressant therapy. These findings suggest a relatively greater benefit of rituximab earlier in the disease course. A placebo-controlled randomized trial to corroborate these findings is warranted.

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Dataset Information

Serum proteomic, peptidomic and metabolomic profiles in myasthenia gravis patients during treatment with Qiangji Jianli Fang.

Publications

Serum proteomic, peptidomic and metabolomic profiles in myasthenia gravis patients during treatment with Qiangji Jianli Fang.

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