Dataset Information

Serum metabolomics of treatment response in myasthenia gravis.

ABSTRACT:

Objective

High-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.

Methods

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 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.

Results

Increased 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.

Interpretation

We 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.

SUBMITTER: Sikorski P

PROVIDER: S-EPMC10564178 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Serum metabolomics of treatment response in myasthenia gravis.

Sikorski Patricia P Li Yaoxiang Y Cheema Mehar M Wolfe Gil I GI Kusner Linda L LL Aban Inmaculada I Kaminski Henry J HJ

PloS one 20231010 10

<h4>Objective</h4>High-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 th ...[more]

PMID: 37816000

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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 metabolomics of treatment response in myasthenia gravis.

Objective

Methods

Results

Interpretation

Publications

Serum metabolomics of treatment response in myasthenia gravis.

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