Background: Individuals meeting the EULAR definition of clinically suspect arthralgia (CSA) are at heightened risk of progression to rheumatoid arthritis (RA). Interrogating immune dysregulation at this preclinical stage offers a unique opportunity to identify the earliest pathogenic events preceding overt disease. Circulating CD19 ⁺ CD24ʰⁱCD38ʰⁱ transitional B cells (cTrB) are dynamically altered across RA disease stage: reduced or unchanged relative to healthy controls (HC) in established RA, yet expanded in untreated early RA before contracting following therapy. However, whether cTrB dysregulation is already present during the CSA phase remains unknown.

Objectives: To examine baseline frequencies of cTr B cells in CSA patients relative to healthy controls and determine changes upon RA progression.

Methods: In this prospective, observational study, peripheral blood was obtained at baseline from patients with CSA and from age- and sex-matched healthy controls. Peripheral blood mononuclear cells were isolated and characterized by flow cytometry. Participants were then monitored until the development of RA or for a maximum of 48 months

Results: During the observation period, 33 of 70 CSA patients (47%) progressed to inflammatory arthritis. Of these, 19 of 33 seropositive CSA patients (58%) and 11 of 37 seronegative CSA patients (30%) met the 2010 ACR/EULAR classification criteria for RA. Among the 37 seronegative individuals, one (3%) developed undifferentiated arthritis and two (5%) developed spondyloarthritis.

Compared with healthy controls (HC), baseline frequencies of circulating transitional B cells (cTrB) were increased in both seropositive (RF and/or ACPA

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; n=33) and seronegative CSA patients (n=37). In addition, circulating CD19

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CD24ˡᵒCD38ˡᵒ mature naïve B cells (cMatN) were elevated in both CSA subgroups, whereas increased frequencies of circulating CD19

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CD27

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CD20

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CD38ʰⁱ plasmablasts (cPlbl) were observed exclusively in seropositive CSA patients.

Baseline cTrB frequencies did not differ between non-progressors, early progressors (<1 year), and late progressors (>1 year). In contrast, very early progressors (<3 months) exhibited significantly higher baseline cTrB frequencies compared with all other groups. At the onset of RA, both seropositive and seronegative progressors demonstrated a further increase in cTrB cell frequencies.

Frequencies of cMatN B cells and cPlbl did not differ between progression groups and remained unchanged at RA onset.

Conclusions: An increased baseline frequency of cTr B cells is apparent in both seropositive and seronegative CSA patients, associates with very early progression (<3 months) and is further upregulated upon RA development

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: Beatriz Nieto-Carvalhal: None declared, Mariana Gutierrez Riart: None declared, Laura Nuño: None declared, Alejandro Villalba: None declared, Marta Novella-Navarro: None declared, Irene Monjo-Henry: None declared, Diana Peiteado: None declared, Eugenio De Miguel: None declared, Maria-Eugenia Miranda-Carus Gebro Pharma, BMS.