Background/Purpose: B-cell over-activation plays a key role in the pathogenesis of rheumatoid arthritis (RA), thus being recognized as a therapeutic target. However, the activation of the B-cell compartment is under the control of a complex network of mediators, including ligands and receptors, expressed as membrane (m) and soluble (s) forms. The main aim of this study was to gain insight into the associations of B-cell related factors and its decoy receptors in RA, focusing on its clinical relevance.

Methods: serum levels of sBLyS, sAPRIL, sBCMA, sTACI, sBLyS-R (BR3), IFNα, MIP1α, TNFα, IL-10, IFNγ and GM-CSF levels were measured by immunoassays in 104 RA patients (EULAR/ACR 2010 criteria) and 33 healthy controls (HC). The gene expression of IFI44, IFI44L, IFI6 and MX1 was measured in peripheral blood and averaged into an IFN score. The membrane BLyS (mBLyS) expression was assessed on B cells, monocytes (MØ), myeloid (mDC) 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 levels (p=0.002) than HC. sBLyS was higher in patients with very early RA (VERA, recruited at onset) compared to those with long-standing disease (p=0.051) and HC (p=0.024). No differences in sTACI and sBLyS-R were observed (p=0.462 and p=0.507). The sBLyS/sBLyS-R ratio was increased in VERA patients compared to HC and patients with established disease, where a positive correlation with DAS28 was noted (r=0.298, p=0.008). Moreover, increased sBLyS/sBLyS-R ratio at onset was associated with poor clinical response after 6 and 12 months (both p<0.050) in VERA patients. IFN score was negatively associated with sBLyS (r=-0.463, p=0.031) in VERA, whereas it was positively associated with sBLyS-R (r=0.271, p=0.029) and sTACI (r=0.210, p=0.050) in patients with established disease. mBLyS expression was increased on B cells, MØ, mDC (all p<0.001) and NØ (p=0.014) in RA, without differences by disease duration. An unsupervised cluster analysis based on sBLyS, sAPRIL, sBCMA, sTACI and sBLyS-R identified 2 clusters (I and II), cluster II being hallmarked by increased sAPRIL and sBCMA levels. Cluster II was overrepresented in RA compared to HC (32/104 vs 3/33, p=0.015). Cluster II RA patients showed increased prevalence of RF (p=0.008) and ACPA (p=0.008) positivity and were more likely treated with anti-TNFa agents (p=0.020) compared to their cluster I counterparts. Moreover, higher IFNα (p=0.035), TNFα (p<0.001), GM-CSF (p<0.001), IL-37 (p=0.015) levels and IFN score (p=0.015) were found in cluster II. Finally, increasing sBLyS (p=0.043) and sBCMA levels (p=0.019) were associated with poor clinical outcome upon TNFα-blockade.

Conclusion: Altered serum levels of B-cell factors are found in RA, with important differences between the very early and established stages. sAPRIL and sBCMA identify a subset of patients with a more severe disease, probably linked to a B-cell over-activation, and inadequate response to TNFα-blockade. A less efficient negative feedback from their decoy receptors may underlie these associations.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/profiling-of-b-cell-related-factors-and-its-decoy-receptors-in-rheumatoid-arthritis-potential-clues-for-patient-stratification/