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Background: Approximately 30% of patients with rheumatoid arthritis (RA) respond poorly to combination therapy of multiple drugs. The molecular mechanisms of different responses to methotrexate + leflunomide + infliximab therapy in patients with RA were explored in this study. Methods: Infliximab was administered to patients with RA whose disease activity score was higher than 5.1 after 1 month of combination therapy with methotrexate and leflunomide. After 14 weeks of undergoing triple therapy, patients with RA were classified as responders and non-responders. Protein profiles at baseline and 14th week were investigated via isobaric tags for relative and absolute quantification (iTRAQ), and proteins with significant differences ≥ 1.2 folds change or ≤ 0.8 folds change were defined as differentially expressed proteins (DEPs). Overlapping DEPs between responders and non-responders were confirmed by parallel reaction monitoring (PRM). Bioinformatic analyses were performed for DEPs. Results: The results revealed 5 non-responders (NRs) and 15 responders (Rs). iTRAQ analysis indicated 13 overlapping DEPs and included 6 opposite change DEPs such as testicular tissue protein Li 70, cofilin 1, fibrinogen beta chain, galectin-10, serotransferrin (TF) and albumin. The difference in serotransferrin between responders and non-responders confirmed by PRM was significant. Verification by PRM indicated that TF was elevated in the Rs group and was reduced in the NRs group. Bioinformatic analysis indicated that serotransferrin was involved in the hypoxia-inducible factor-1 pathway and ferroptosis. Conclusion: Serotransferrin-related molecular mechanism may be a new direction to study refractory RA. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by progressive joint erosion. Tumor necrosis factor (TNF) antagonists are the most widely used biological disease-modifying anti-rheumatic drug in RA. However, there continue to be one third of RA patients who have poor or no response to TNF antagonists. Following consideration of the uncertainty of therapeutic effects and the high price of TNF antagonists, it is worthy to predict the treatment responses before anti-TNF therapy. According to the comparisons between the responders and non-responders to TNF antagonists by omic technologies, such as genomics, transcriptomics, proteomics, and metabolomics, rheumatologists are eager to find significant biomarkers to predict the effect of TNF antagonists in order to optimize the personalized treatment in RA. [ABSTRACT FROM AUTHOR]

• Aimed to identify biomarkers for predicting the efficacy of triple therapy to RA. • iTRAQ identified 51 DEPs between responders and non-responders to triple therapy. • Targeted mass spectrometry by PRM identified 10 candidate biomarkers. • 3 of 10 candidates were confirmed as predictive biomarkers. Patients with rheumatoid arthritis (RA) usually receive triple therapy with methotrexate (MTX), leflunomide (LEF) and infliximab (IFX), but nearly one-third of them do not respond to triple therapy. This study aimed to identify biomarkers for predicting the efficacy of triple therapy to optimize personalized treatment of RA. All 20 enrolled patients met 2010 ACR/EULAR criteria for RA and were classified into good, moderate and non-responders (GR, MR, NR) for triple therapy. The Responders (R) were defined as the sum of GR and MR. Protein profiles of 4 responders and 4 non-responders were investigated via isobaric tags for relative and absolute quantification (iTRAQ), and differentially expressed proteins (DEPs) with high-confidence peptides were validated in 15 responders and 5 non-responders by parallel response monitoring (PRM). iTRAQ identified 51 DEPs between responders and non-responders (p < 0.05, fold change >±1.2). The top five up-regulated DEPs were B7Z7M2, A0A087WZR4, Q53FL1, P08254 and G3V2V8, while the top five down-regulated proteins were Q6MZX9, B3KP77, P0DJI9, P0DJI8 and P02787. Targeted mass spectrometry by PRM identified 10 candidate biomarkers, and 3 DEPs including fibrinogen beta chain, epididymal secretory protein Li 282 and testicular tissue protein Li 70 were confirmed as predictive biomarkers. This study demonstrated the feasibility of exploring biomarkers by applying iTRAQ and PRM mass spectrometry techniques, and a panel of biomarkers were identified to predict clinical response of IFX + MTX + LEF treatment in active RA patients. [ABSTRACT FROM AUTHOR]