Background/Purpose: Among the best known disease-modifying antirheumatic drugs, Methotrexate (MTX) is one of the most effective and widely used medications. It is used as a general first-choice drug in rheumatoid arthritis (RA), although some patients will not respond to this treatment and it is not free from side effects. The purpose of this work is to identify circulating proteins that could be useful to predict the patient’s response to MTX.

Methods: Serum samples from patients enrolled in the Pathobiology of Early Arthritis Cohort (PEAC) were collected before treatment with MTX. Response to therapy was determined after 6 months by calculating the initial and final DAS28 of the patients. Their classification was performed following the EULAR response criteria. Sixty samples at baseline from this cohort (30 good responders and 30 non-responders) were depleted from the 14 most abundant proteins by affinity chromatography to remove background. Then, they were analysed by reversed-phase nanoliquid chromatography coupled to mass spectrometry using a SWATH strategy in a tripleTOF MS (Sciex). The quantitative data obtained in this proteomic analysis were processed using the ProteinPilot 5.0.1 and PeakView 2.1 software (Sciex). Machine learning analyses were performed on a train set of 30 samples (15 responders and 15 non-responders) via support vector machine (SVM) using the Classyfire, e1071 and caret R packages. Results were verified in an independent set of 24 samples by a two-stage support vector machine (TSSVM) with RBF kernel and 10 cross-fold validation for each meta-model.

Results: The proteomic analysis led to the identification and quantification of 229 proteins that were common between the screening and validation sets. Independent screening and validation data sets were pre-processed by PCA for dimension reduction. Then, results were analyzed by machine learning tools, leading to the definition of a panel of 8 proteins (one of them involved in MTX metabolism and two in the regulation of the immune response) that classifies at baseline the groups of responders and non-responders to MTX with strong agreement (Kappa>0.80), very high accuracy and good relevant metrics (Table 1).

Conclusion: We have defined a panel of circulating proteins useful to predict the response to MTX therapy in rheumatoid arthritis patients.

Table 1. Metrics of the classification performance of the 8-protein panel identified in this work to predict response of the patient to MTX. Cut-off for significance was p-value < 0.05.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-a-protein-profile-useful-to-predict-response-to-methotrexate-in-early-rheumatoid-arthritis-patients/