Abstract
BackgroundSystemic inflammation in rheumatoid arthritis (RA) is associated with metabolic changes. We used nuclear magnetic resonance (NMR) spectroscopy–based metabolomics to assess the relationship between an objective measure of systemic inflammation [C-reactive protein (CRP)] and both the serum and urinary metabolome in patients with newly presenting RA.MethodsSerum (n=126) and urine (n=83) samples were collected at initial presentation from disease modifying anti-rheumatic drug naïve RA patients for metabolomic profile assessment using 1-dimensional 1H-NMR spectroscopy. Metabolomics data were analysed using partial least square regression (PLS-R) and orthogonal projections to latent structure discriminant analysis (OPLS-DA) with cross validation.ResultsUsing PLS-R analysis, a relationship between the level of inflammation, as assessed by CRP, and the serum (p=0.001) and urinary (p<0.001) metabolome was detectable. Likewise, following categorisation of CRP into tertiles, patients in the lowest CRP tertile and the highest CRP tertile were statistically discriminated using OPLS-DA analysis of both serum (p=0.033) and urinary (p<0.001) metabolome. The most highly weighted metabolites for these models included glucose, amino acids, lactate, and citrate. These findings suggest increased glycolysis, perturbation in the citrate cycle, oxidative stress, protein catabolism and increased urea cycle activity are key characteristics of newly presenting RA patients with elevated CRP.ConclusionsThis study consolidates our understanding of a previously identified relationship between serum metabolite profile and inflammation and provides novel evidence that there is a relationship between urinary metabolite profile and inflammation as measured by CRP. Identification of these metabolic perturbations provides insights into the pathogenesis of RA and may help in the identification of therapeutic targets.
Highlights
rheumatoid arthritis (RA) is a systemic inflammatory disease characterised by synovial inflammation and bone damage
Orthogonal Partial Least Square Discriminant Analysis (OPLS-DA) and Partial Least Square Regression (PLS-R) were used to perform supervised multivariate analyses. For both the PCA and OPLS-DA, a comparison was made between those individuals with low and high C-reactive protein (CRP) values comparing patients in the lowest and highest CRP tertile groups
Over-representation analysis (Figure 4) in pathway-associated metabolite sets indicated that amongst the multiple pathways which were implicated, methylhistidine metabolism, the urea cycle and the glucose alanine cycle were the most overrepresented in the serum of patients with elevated CRP. These results suggested that perturbed energy and amino acid metabolism in the serum are key characteristics of RA patients with elevated CRP
Summary
RA is a systemic inflammatory disease characterised by synovial inflammation and bone damage. Systemic inflammation associated with early RA is responsible for significant extra-articular morbidity with an increased prevalence of stroke, heart failure [6], chronic obstructive pulmonary disease, asthma and interstitial lung disease [7] amongst early RA patients compared to matched controls. There is evidence of systemic changes in metabolism several years prior to onset of overt disease, which may be driven by early immune processes [8]. Systemic inflammation in rheumatoid arthritis (RA) is associated with metabolic changes. We used nuclear magnetic resonance (NMR) spectroscopy–based metabolomics to assess the relationship between an objective measure of systemic inflammation [C-reactive protein (CRP)] and both the serum and urinary metabolome in patients with newly presenting RA
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