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Randomized Controlled Trial
. 2018 Oct 15;20(1):230.
doi: 10.1186/s13075-018-1729-2.

Baseline metabolic profiles of early rheumatoid arthritis patients achieving sustained drug-free remission after initiating treat-to-target tocilizumab, methotrexate, or the combination: insights from systems biology

Xavier M Teitsma  1 , Wei Yang  2 , Johannes W G Jacobs  3 , Attila Pethö-Schramm  4 , Michelle E A Borm  5 , Amy C Harms  2   6 , Thomas Hankemeier  2   6 , Jacob M van Laar  3 , Johannes W J Bijlsma  3 , Floris P J G Lafeber  3
Affiliations
Randomized Controlled Trial

Baseline metabolic profiles of early rheumatoid arthritis patients achieving sustained drug-free remission after initiating treat-to-target tocilizumab, methotrexate, or the combination: insights from systems biology

Xavier M Teitsma et al. Arthritis Res Ther. .

Abstract

Background: We previously identified, in newly diagnosed rheumatoid arthritis (RA) patients, networks of co-expressed genes and proteomic biomarkers associated with achieving sustained drug-free remission (sDFR) after treatment with tocilizumab- or methotrexate-based strategies. The aim of this study was to identify, within the same patients, metabolic pathways important for achieving sDFR and to subsequently study the complex interactions between different components of the biological system and how these interactions might affect the therapeutic response in early RA.

Methods: Serum samples were analyzed of 60 patients who participated in the U-Act-Early trial (ClinicalTrials.gov number NCT01034137) and initiated treatment with methotrexate, tocilizumab, or the combination and who were thereafter able to achieve sDFR (n = 37); as controls, patients were selected who never achieved a drug-free status (n = 23). Metabolomic measurements were performed using mass spectrometry on oxidative stress, amine, and oxylipin platforms covering various compounds. Partial least square discriminant analyses (PLSDA) were performed to identify, per strategy arm, relevant metabolites of which the biological pathways were studied. In addition, integrative analyses were performed correlating the previously identified transcripts and proteins with the relevant metabolites.

Results: In the tocilizumab plus methotrexate, tocilizumab, and methotrexate strategy, respectively, 19, 13, and 12 relevant metabolites were found, which were subsequently used for pathway analyses. The most significant pathway in the tocilizumab plus methotrexate strategy was "histidine metabolism" (p < 0.001); in the tocilizumab strategy it was "arachidonic acid metabolism" (p = 0.018); and in the methotrexate strategy it was "arginine and proline metabolism" (p = 0.022). These pathways have treatment-specific drug interactions with metabolites affecting either the signaling of interleukin-6, which is inhibited by tocilizumab, or affecting protein synthesis from amino acids, which is inhibited by methotrexate.

Conclusion: In early RA patients treated-to-target with a tocilizumab- or methotrexate-based strategy, several metabolites were found to be associated with achieving sDFR. In line with our previous observations, by analyzing relevant transcripts and proteins within the same patients, the metabolic profiles were found to be different between the strategy arms. Our metabolic analysis further supports the hypothesis that achieving sDFR is not only dependent on predisposing biomarkers, but also on the specific treatment that has been initiated.

Trial registration: ClinicalTrials.gov, NCT01034137 . Registered on January 2010.

Keywords: Drug-free remission; Metabolomics; Methotrexate; Rheumatoid arthritis; Tocilizumab.

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Conflict of interest statement

Ethics approval and consent to participate

The medical ethics research committee of the University Medical Center Utrecht approved the study for all participating hospitals. All patients signed informed consent before study entry.

Consent for publication

Not applicable.

Competing interests

The department of the authors who included patients (JWGJ and JWJB) in the U-Act-Early trial received reimbursements from Roche Nederland BV. JWJB reported grants and fees from Roche, AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, and UCB. JMvL received fees from Arthrogen, MSD, Pfizer, Eli Lilly, and BMS and research grants from Astra Zeneca, Roche-Genentech. FPJGL reports grants from Roche. AP-S is an employee of F Hoffmann-La Roche and MEAB is an employee of Roche Nederland BV. XMT, WY, ACH, and TH declare no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Mean (SE) DAS28-ESR over time in those achieving sDFR (continuous line) vs controls (dotted line) within the three strategy arms. DAS28 disease activity score assessing 28 joints, ESR erythrocyte sedimentation rate, MTX methotrexate, sDFR sustained drug-free remission, SE standard error, TCZ tocilizumab
Fig. 2
Fig. 2
Pathway analysis within the identified metabolites in the (a) tocilizumab plus methotrexate, (b) tocilizumab, and (c) methotrexate strategy arms. Metabolites depicted in red nodes have, on average, lower concentration in the sDFR group compared to controls; those depicted in green nodes have a higher concentration. *p ≤ 0.10, **p ≤ 0.05, ***p ≤ 0.01. Metabolites not included in the top three most relevant pathways are not displayed
Fig. 3
Fig. 3
Network correlation between transcriptomic (gray nodes), proteomic (orange nodes), and metabolomic (blue nodes) biomarkers in the (a) tocilizumab plus methotrexate, (b) tocilizumab, and (c) methotrexate strategy arms. Only significant transcriptomic–proteomic and proteomic–metabolomic correlations are displayed
See this image and copyright information in PMC

Comment in

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