Plasma Metabolome Normalization in Rheumatoid Arthritis Following Initiation of Methotrexate and the Identification of Metabolic Biomarkers of Efficacy

Matthew R Medcalf; Pooja Bhadbhade; Ted R Mikuls; James R O'Dell; Rebekah L Gundry; Ryan S Funk

doi:10.3390/metabo11120824

Plasma Metabolome Normalization in Rheumatoid Arthritis Following Initiation of Methotrexate and the Identification of Metabolic Biomarkers of Efficacy

Metabolites. 2021 Nov 30;11(12):824. doi: 10.3390/metabo11120824.

Authors

Matthew R Medcalf¹, Pooja Bhadbhade², Ted R Mikuls^{3

4}, James R O'Dell^{3

4}, Rebekah L Gundry⁵, Ryan S Funk^{1

6}

Affiliations

¹ Department of Pharmacy Practice, University of Kansas, Kansas City, KS 66160, USA.
² Division of Allergy, Clinical Immunology and Rheumatology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
³ Division of Rheumatology & Immunology, Department of Internal Medicine, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA.
⁴ VA Nebraska-Western IA Health Care System, Omaha, NE 68198, USA.
⁵ CardiOmics Program, Center for Heart and Vascular Research, Division of Cardiovascular Medicine, Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁶ Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.

Abstract

Methotrexate (MTX) efficacy in the treatment of rheumatoid arthritis (RA) is variable and unpredictable, resulting in a need to identify biomarkers to guide drug therapy. This study evaluates changes in the plasma metabolome associated with response to MTX in RA with the goal of understanding the metabolic basis for MTX efficacy towards the identification of potential metabolic biomarkers of MTX response. Plasma samples were collected from healthy control subjects (n = 20), and RA patients initiating MTX therapy (n = 20, 15 mg/week) before and after 16 weeks of treatment. The samples were analyzed by a semi-targeted metabolomic analysis, and then analyzed by univariate and multivariate methods, as well as an enrichment analysis. An MTX response was defined as a clinically significant reduction in the disease activity score in 28 joints (DAS-28) of greater than 1.2; achievement of clinical remission, defined as a DAS-28 < 2.6, was also utilized as an additional measure of response. In this study, RA is associated with an altered plasma metabolome that is normalized following initiation of MTX therapy. Metabolite classes found to be altered in RA and corrected by MTX therapy were diverse and included triglycerides (p = 1.1 × 10^-16), fatty acids (p = 8.0 × 10^-12), and ceramides (p = 9.8 × 10^-13). Stratification based on responses to MTX identified various metabolites differentially impacted in responders and non-responders including glucosylceramides (GlcCer), phosphatidylcholines (PC), sphingomyelins (SM), phosphatidylethanolamines (PE), choline, inosine, hypoxanthine, guanosine, nicotinamide, and itaconic acid (p < 0.05). In conclusion, RA is associated with significant alterations to the plasma metabolome displaying at least partial normalization following 16 weeks of MTX therapy. Changes in multiple metabolites were found to be associated with MTX efficacy, including metabolites involved in fatty acid/lipid, nucleotide, and energy metabolism.

Keywords: biomarkers; metabolism; metabolomics; methotrexate; plasma metabolome; rheumatoid arthritis.

Abstract

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