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

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

doi:10.3390/metabo11120824

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.

Highlights

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that primarily impacts joints but can affect a wide variety of tissues and organs [1]
No reliable biomarkers exist that allow for the stratification of patients according to who will respond to MTX therapy or who will require alternative disease modifying antirheumatic drug (DMARD) [6]
The data obtained from this study were intended for the generation of hypothesis regarding the effects on the plasma metabolome involved in RA progression and in response to MTX therapy

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that primarily impacts joints but can affect a wide variety of tissues and organs [1]. Methotrexate (MTX) remains the cornerstone disease modifying antirheumatic drug (DMARD), due to its efficacy and economic merits [4]. MTX has been proven to slow the progression of RA while minimizing damage to tissues and joints. MTX therapy is often characterized by a highly variable response and a delayed onset of action. Two-thirds of patients fail to have an adequate response to MTX therapy following six months of therapy [5]. The variable and unpredictable profile of MTX response has indicated a need for the identification of clinical biomarkers to guide drug therapy. No reliable biomarkers exist that allow for the stratification of patients according to who will respond to MTX therapy or who will require alternative DMARDs (e.g., biologics) [6]. A major barrier to the identification of biomarkers of MTX response is an incomplete understanding of the molecular basis through which MTX mediates pharmacological effects in the treatment of RA [1]

Methods

Results

Discussion

Conclusion