Session Type: Abstract Submissions (ACR)
4-1BB is induced on T cells after antigen encounter and promotes clonal expansion and accumulation of high numbers of antigen-specific effector-type T cells primarily in the joint. This leads to survival of CD4 T cells and CD8 T cells and enhance TCR-dependent activities such as cytokine production. 4-1BB has previously been linked to rheumatoid arthritis (RA). We examined the role of 4-1BB in early treatment naïve RA (eRA, the OPERA cohort) and chronic RA (cRA).
Soluble 4-1BB was measured by ELISA in plasma from 77 treatment naïve eRA patients (disease < 3 month), at baseline, after 3 months, and after 12 months of treatment in addition to age and gender matched healthy volunteers (HV) (n=54). Treatment was methotrexate + placebo (MTX) (n=41) or MTX + Adalimumab (ADA) (n=36). Clinical disease was assessed by: DAS28, CRP, number of swollen (SJ40) and tender joints (TJ40), IgM-RF and ACPA. In addition s4-1BB was also measured by ELISA in both plasma and synovial fluid (SF) from 8 cRA patients (disease duration > 6 years (24 (7-48) years) with active disease.
Membrane bound 4-1BB was measured on peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) by flow cytometry in cRA, and in PBMC from HV (n=9). Paired samples were compared by Wilcoxon signed rank test, non-paired samples by Mann-Whitney rank sum test. Correlations were tested using Spearman’s rho (ρ). Data are expressed as median (IQR).
In eRA plasma levels of s4-1BB were significantly elevated at baseline (9.8 (4.0-23.0) pg/ml) compared with HV (4.0 (4.0-4.9) pg/ml) (P < 0.01). After 12 months treatment 4-1BB levels were similar to levels in HV. No differences were seen in the s4-1BB plasma levels over time between the ADA and MTX group. We observed correlation with baseline s4-1BB with SJ40 (ρ =0.3) and DAS28 at 24 month (ρ =0.3) (both p<0.05)). A significant association with the presence of IgM-RF was observed.
In cRA patients significantly elevated levels were measured in the SF ((102 (44.9 -134.4) pg/ml) compared with plasma ((5.24 (3.91-40.3) pg/ml) (P < 0.01). Further, plasma s4-1BB showed a strong correlation with the corresponding levels in the synovial fluid. (ρ=0.7, p< 0.01).
In cRA the expression of 4-1BB on the total number of T cells was significantly higher in SFMCs (4.12% (2.24-12.52) %) compared with PBMCs (1.55% (0.93-3.57) %) and PBMCs from HV (0.91 (0.53-2.35) %) (both p < 0.01). Further 4-1BB was primarily expressed by CD45RO+ T-cells.
4-1BB plasma levels were significantly elevated in treatment naïve eRA patients and decreased to levels comparable with HV within 12 months of successful treatment.
The discovery that s4-1BB is association with number of swollen joints and DAS28 as far as 2 years post treatment initiation, and since the s4-1BB in plasma reflects the levels seen in the SF in active cRA, all points to 4-1BB being a potential marker of disease activity. 4-1BB expression is mainly present on activated T cells in the joint of patients with active cRA. This confirms that 4-1BB is present in the inflamed joint in cRA.
Taken together this supports a central role of 4-1BB in the T cell activity in the inflamed joint; the centre of disease development in eRA.
M. A. Nielsen,
Janssen Pharmaceutica Product, L.P.,
M. L. Hetland,
Abbott/Abbvie, Centocor, Merck, Schering-Plough,
Abbott/Abbvie, BMS, Boehringer-Ingelheim, Eli-Lilly, Centocor, GSK, Janssen, Merck, Mundipharma, Novo, Pfizer, Schering-Plough, Roche UCB, and Wyeth,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/soluble-4-1bb-is-a-marker-of-joint-involvement-and-disease-activity-in-rheumatoid-arthritis/