โก Quick Summary
This study utilized integrative multi-omic profiling to reveal distinct immune and metabolic signatures in blood between ACPA-negative and ACPA-positive rheumatoid arthritis patients. The findings suggest that ACPA status alone may not fully capture the biological diversity of rheumatoid arthritis, highlighting the need for more nuanced diagnostic approaches.
๐ Key Details
- ๐ Cohort Size: 40 ACPA- RA patients, 40 ACPA+ RA patients, and 40 healthy controls
- ๐งฌ Techniques Used: High-throughput proteomic and metabolomic profiling
- โ๏ธ Analysis Methods: Statistical comparisons, pathway enrichment analyses, and machine learning frameworks
- ๐ Performance: Machine learning achieved an AUC โฅ 0.90 in distinguishing RA subgroups
๐ Key Takeaways
- ๐ฌ Distinct Biomarkers: ACPA- and ACPA+ RA patients exhibited unique plasma proteomic and metabolomic signatures.
- ๐ก Key Proteins: Complement proteins (CFB, CFHR5, F9) and IL1RN were elevated in ACPA- RA.
- ๐งช Metabolic Differences: Variations in lipid and pyrimidine metabolism were observed between the two RA subgroups.
- ๐ Correlation Insights: Differential associations between molecular features and clinical inflammatory markers were identified.
- ๐ค Machine Learning Advantage: Integrative approaches outperformed single-omic models in classification tasks.
- ๐ Broader Implications: Findings may enhance RA diagnostics and inform tailored disease management strategies.

๐ Background
Rheumatoid arthritis (RA) is a complex autoimmune disorder characterized by inflammation and joint damage. Traditionally, RA has been classified based on the presence of anti-citrullinated protein antibodies (ACPA). However, this binary classification may overlook the biological heterogeneity present within RA subgroups. Understanding these differences is crucial for developing more effective diagnostic and treatment strategies.
๐๏ธ Study
The study involved a well-characterized cohort of RA patients and healthy controls, focusing on high-throughput proteomic and metabolomic profiling of plasma samples. By employing advanced statistical and machine learning techniques, the researchers aimed to uncover subgroup-specific molecular signatures that could enhance our understanding of RA’s biological complexity.
๐ Results
The results indicated that ACPA- and ACPA+ RA patients have distinct plasma profiles, with specific proteins and metabolites differing significantly between the groups. Notably, the machine learning framework demonstrated high classification performance, achieving an AUC of 0.90 or greater, underscoring the potential of multi-omic approaches in clinical settings.
๐ Impact and Implications
The implications of this study are profound. By revealing the distinct immune and metabolic signatures associated with ACPA- and ACPA+ RA, the research paves the way for more precise diagnostic tools and treatment strategies. This could lead to improved patient outcomes and a better understanding of RA’s underlying mechanisms, ultimately enhancing disease management.
๐ฎ Conclusion
This study highlights the importance of considering biological heterogeneity in rheumatoid arthritis beyond ACPA status. The use of multi-omic profiling not only enhances our understanding of RA but also opens new avenues for personalized medicine. Continued research in this area is essential for refining diagnostic and therapeutic approaches in RA.
๐ฌ Your comments
What are your thoughts on the findings of this study? How do you think multi-omic profiling could change the landscape of rheumatoid arthritis management? ๐ฌ Join the conversation in the comments below or connect with us on social media:
Integrative multi-omic profiling in blood reveals distinct immune and metabolic signatures between ACPA-negative and ACPA-positive rheumatoid arthritis.
Abstract
OBJECTIVE: To investigate whether patients with ACPA-negative (ACPA-) and ACPA-positive (ACPA+) rheumatoid arthritis (RA) exhibit distinct immune and metabolic profiles in blood, using integrative proteomic and metabolomic analyses. By uncovering subgroup-specific molecular signatures, we aim to improve the biological understanding of RA heterogeneity and support the development of more precise diagnostic and stratification strategies.
METHODS: We performed high-throughput proteomic and metabolomic profiling on plasma from a well-characterized cohort comprising 40 patients with ACPA- RA, 40 patients with ACPA+ RA, and 40 healthy controls. To identify key immune and metabolic differences, we applied statistical comparisons, pathway enrichment analyses, and network inference methods. Additionally, an integrative network-based machine learning framework was used to distinguish RA subgroups from controls based on plasma molecular profiles.
RESULTS: ACPA- and ACPA+ RA exhibited distinct plasma proteomic and metabolomic biomolecular signatures. Complement proteins (CFB, CFHR5, and F9) and the anti-inflammatory cytokine IL1RN were exclusively elevated in ACPA- RA and remained distinct in a treatment-naรฏve sub-cohort. Metabolomic analysis revealed subgroup-specific differences in lipid and pyrimidine metabolism, including contrasting patterns in bilirubin-derived metabolites. Correlation analyses identified differential associations between molecular features and clinical inflammatory markers across RA subgroups. An integrative machine learning framework incorporating multi-omic features achieved high classification performance in cross-validation (AUC โฅ 0.90), outperforming models based on single-omic data.
CONCLUSION: This study suggests that ACPA status may not fully capture the biological heterogeneity between ACPA- and ACPA+ RA subgroups, indicating additional immune and metabolic distinctions that warrant further investigation. Our findings highlight the potential of multi-omic profiling to enhance RA diagnostics, refine disease stratification, and inform subgroup-specific disease management strategies.
Author: [‘Hur B’, ‘Gupta VK’, ‘Oh M’, ‘Zeng H’, ‘Crowson CS’, ‘Warrington KJ’, ‘Myasoedova E’, ‘Kronzer VL’, ‘Davis JM’, ‘Sung J’]
Journal: Front Immunol
Citation: Hur B, et al. Integrative multi-omic profiling in blood reveals distinct immune and metabolic signatures between ACPA-negative and ACPA-positive rheumatoid arthritis. Integrative multi-omic profiling in blood reveals distinct immune and metabolic signatures between ACPA-negative and ACPA-positive rheumatoid arthritis. 2025; 16:1667662. doi: 10.3389/fimmu.2025.1667662