Background/Purpose: Using musculoskeletal ultrasound (US) to assess joint erosions and disease activity in patients with seropositive rheumatoid arthritis (RA) an atypical subgroup was identified with active disease demonstrated by significant Power Doppler, but normal C-reactive protein (CRP) and erythrocyte sedimentation rate levels. We questioned whether this presentation was associated with delayed diagnosis or relative under treatment, risking worse disease outcome and/or disability. We hypothesized that understanding the underlying immune pathology in this atypical subset could directly influence therapeutic targeting in patients whose needs are not currently met. We aim to stratify patients based on their immune signature to identify new treatment algorithms and therapeutic targets.

Methods: 44 RA patients with active synovitis were recruited, defined by ≥1 joint with Power Doppler detected by US, 29 had normal (n)CRP (≤5mg/L) and 15 had high (h)CRP (>5mg/L) levels. Peripheral blood mononuclear cells (PBMCs), serum and detailed clinical data were collected. 18 age and sex matched healthy donors were also analyzed. Multiple 14-colour flow cytometry panels were used to perform in-depth PBMC immunophenotyping. Serum and intracellular cytokines were assessed using Cytometric Bead Array and flow cytometry. Plasma was subjected to SOMAscan™ (Slow Off-rate Modified Aptamer) Proteomic Assay. Data was analyzed using cluster analysis (partitioning and hierarchical agglomerative algorithms) and correlation analysis (using a shrinkage estimator of the partial correlation matrix).

Results:  nCRP patients had increased erosion accrual rate compared to hCRP patients (p=0.022) reflecting more disease-associated joint damage, while other clinical and laboratory parameters were identical. However, nCRP patients were able to mount a CRP response to infection. Serum IL-6 and IL-1β, pro-inflammatory cytokines known to trigger CRP production and support T-cell activation, were significantly elevated in both patient groups compared to healthy donors (p=<0.001) suggesting either defects in downstream IL-6 signaling or the disease mechanism may be IL-6-independent in nCRP patients. In support of this, nCRP patients had an anti-inflammatory phenotype characterized by significantly increased regulatory T-cells (Tregs) (p=0.014) with increased CD161 expression, known to be inversely correlated with CRP levels and associated with increased Treg suppressive capacity. Alternatively, hCRP patients had the expected activated T-cell phenotype including increased central memory T-cells (p=0.024) and Th17 populations. Preliminary proteomic analysis identified significant increases in complement components, serum amyloid P (SAP) and CRP in the hCRP compared to nCRP patients. Strikingly, serum amyloid A, an acute phase protein that has different ligands to CRP and SAP was significantly increased in both patient groups.

Conclusion: This study stratifies distinct patient subgroups using detailed immunophenotyping and proteomic signatures. We have identified altered immunopathological mechanisms in nCRP patients which could translate to improved patient-specific therapies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-unique-immune-signature-in-patients-with-active-rheumatoid-arthritis-but-normal-c-reactive-protein-levels-potential-for-new-therapeutic-targets/