Background/Purpose: B cell compartment plays a key role in the pathogenesis of rheumatoid arthritis (RA). Activation and survival of B cell largely rely on the BLyS-APRIL system, including ligands and receptors, both expressed as membrane (m) and soluble (s) forms. The main aim of this study was to analyze the role of the BLyS-APRIL system in RA, with a special focus on its clinical relevance.

Methods: sBLyS, sAPRIL, sBCMA, sTACI, IFNα, MIP1α, TNFα, IL-10, IFNγ, IL-8, IL-37 and GM-CSF levels were measured by immunoassays in serum samples from 104 RA patients (EULAR/ACR 2010 criteria) and 33 healthy controls (HC). The membrane BLyS (mBLyS) expression was assessed on B cells, monocytes (MØ), myeloid (mDC) and plasmacytoid (pDC) dendritic cells and neutrophils (NØ) by flow cytometry in blood samples. A group of biological-naïve RA patients was prospectively followed for 3 months upon TNFα-blockade.

Results: RA patients exhibited increased sAPRIL (p<0.001) and sBCMA serum levels (p=0.002) than HC. sBLyS was higher in patients with early arthritis (recruited at onset) compared to those with long-standing disease (p=0.051) and HC (p=0.024). Levels of sTACI did not differ between patients and controls (p=0.462). mBLyS expression was increased on B cells (p=0.002), MØ (p<0.001), mDC (p<0.001) and NØ (p=0.014) in RA. By means of an unsupervised cluster analysis based on sBLyS, sAPRIL, sBCMA and sTACI, two clusters were identified (clusters I and II), cluster II being hallmarked by increased sAPRIL and sBCMA serum levels. Cluster II was found in 26 (25.0%) RA patients but was not observed in the HC group (p=0.001). Cluster II RA patients showed increased RF (p=0.002) and ACPA (p=0.001) positivity and were less likely to be treated with methotrexate (p=0.028) but more likely with anti-TNFα agents (p=0.013) compared to their cluster I counterparts. Cluster II was associated with higher DAS28 (p<0.050) but no difference in disease duration was observed (p=0.159). Additionally, higher IL-10 (p=0.060), IFNα (p=0.005), MIP1α (p=0.042), TNFα (p=0.006) and GM-CSF (p=0.008) levels were registered in cluster II. Further analyses revealed that sTACI was negatively associated with DAS28 score (r=-0.283, p=0.014) and positively with IL-10 serum levels (r=0.233, p=0.040) in patients within cluster I. On the contrary, in cluster II, APRIL was positively correlated with mBLyS expression on B cells (r=0.786, p=0.036), whereas sBLyS was associated with DAS28 (r=0.281, p=0.016). Also, IFNα serum levels paralleled those of sTACI (r=-0.636, p<0.001) in these patients. Finally, increasing sBLyS (p=0.043) and sBCMA levels (p=0.019) upon TNFα-blockade were associated with poor clinical outcome.

Conclusion: APRIL and sBCMA identify a subset of patients with a more severe disease, probably linked to a B cell hyperactivation status. APRIL and sBCMA may be promising biomarkers for patient stratification to B-cell targeted therapy in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sapril-and-sbcma-as-potential-biomarkers-of-b-cell-hyperactivation-in-rheumatoid-arthritis-a-cluster-analysis-approach/