P142 Cytomegalovirus seropositivity is associated with an increased frequency of highly differentiated T effector memory cells re-expressing CD45RA (Temra) and persistent disease refractory to anti-TNF therapy in rheumatoid arthritis
Authors: Yeoh Su-Ann , Kimpton James , Shipa Muhammad , Hawkins Ellie , Akbar Arne , Ehrenstein Michael 
Published: April 2023

Abstract

Background/Aims
The role of highly differentiated T effector memory re-expressing CD45RA (Temra) in rheumatoid arthritis (RA) is unclear, including whether they can be used as a marker of persistent disease activity. Our aim was to investigate whether peripheral blood Temra frequency can be used to identify RA patients with active disease refractory to anti-TNF therapy. As cytomegalovirus (CMV) has been reported to be associated with the expansion of Temra as well as implicated in RA pathogenesis, we also explored the relationship between serum CMV immunoglobulin (IgG) status, Temra, and remission status.

Methods
A cross-sectional cohort of RA patients on anti-TNF therapy were recruited. Patients were stratified based on remission status. Remission was defined as no recorded DAS28-CRP≥2.4, no swollen joints, no C-reactive protein (CRP) &gt;5mg/L, and on a stable DMARD dose and no reported disease flare/loss of remission in the last 6 months before recruitment. Patients on abatacept or on conventional DMARDs only were recruited as comparison groups. Peripheral blood mononuclear cells (PBMC) were analysed by flow cytometry. Serum CMV IgG was analysed by ELISA. Two-tailed Mann-Whitney U test or unpaired t-test were used to obtain unadjusted values, analysis of variance (ANOVA) of log-transformed data to obtain age-adjusted values, Spearman’s rank correlation to compare correlation between two variables, Fisher’s exact test to compare proportions.

Results
Thirty-six anti-TNF, 12 abatacept, and 16 patients on conventional synthetic DMARDs (csDMARDs) only were recruited. A higher proportion of CD4 and CD8 Temra (age-adjusted p = 0.004 and p = 0.0007 respectively) was observed in RA patients on anti-TNF with persistent disease compared to those in remission. This difference in Temra frequency was not observed in patients treated with csDMARDs only or abatacept. CD4 and CD8 Temra frequency correlated positively with CMV IgG levels (Spearman r = 0.8987, p &lt; 0.0001 and Spearman r = 0.7211, p &lt; 0.0001 respectively). There was a strikingly high proportion of anti-TNF patients with persistent disease who were CMV seropositive compared to anti-TNF patients in remission (93% versus 42%, Fisher’s exact test, p = 0.009). This difference was less marked and not significant in the other treatment groups.

Conclusion
The increased CMV seropositivity and Temra frequency in the context of persistent disease only in anti-TNF treated patients may provide a causal link between Temra and RA pathogenesis refractory to anti-TNF treatment.
Disclosure
S. Yeoh: Grants/research support; S.A.Y. has received funding for research from Versus Arthritis, Royal College of Physicians, Rosetrees Trust, University College London Hospitals NIHR BRC and UCLH charities. J. Kimpton: None. M. Shipa: Grants/research support; M.S. has received funding for research from Versus Arthritis and GSK. E. Hawkins: None. A. Akbar: Grants/research support; A.A. has received funding for research from the Medical Research Council and the Leo Skin Foundation (Denmark). M. Ehrenstein: None.