Introduction Rheumatoid arthritis (RA) develops upon aberrant activation of the immune system mainly due to failure of self-tolerance mechanisms.¹ Abatacept, approved for RA treatment, a recombinant fusion protein of the extracellular domain of human cytotoxic T lymphocyte antigen 4 (CTLA4), restricts T cell activation by blocking interaction of CD80/CD86 on dendritic cells (DCs) to CD28 on T cells.² In clinical practice, approximately 40–50% of RA patients treated with abatacept, respond to therapy in the first 6 months.³ Development of a predictor of response is of clinical and immunological significance.

Objectives Herein, we sought to investigate for early biomarkers of response to abatacept, based on a detailed immunological profile of peripheral blood cells and cytokines.

Methods RA patients (ACR/EULAR 2010 criteria) who started abatacept due to highly active disease, were recruited to perform immunological studies at baseline, 3 and 6 months of therapy. Peripheral blood mononuclear cells (PBMCs) were isolated and pathogenic IL-17 and IFN-γ producing CD4+ T cells (Th1, Th17), regulatory (Tregs) T cell subsets as well as myeloid cell populations, like DCs and myeloid derived suppressor cells (MDSCs) were characterized using flow cytometry. Response to therapy (remission or low disease activity) was assessed based on the “Swollen joints” value.

Results We studied 21 patients (mean age 60 years, 86% women, 48% rheumatoid factor or anti-citrullinated protein antibody positive). After 6 months of treatment, 45% of them attained remission or low disease activity. Notably, baseline levels of Th17 were statistically significant decreased in peripheral blood of patients in remission or low disease activity compared to those with active disease at 6 months of treatment (1.29±0.18% versus 2.44±0.41%, p=0.0482). Baseline levels of Th1 and Foxp3⁺Tregs were comparable between responders and non-responders. No significant differences in CD14^intCD15⁺CD33⁺ MDSCs or CD3^-HLADR⁺ DCs were observed.

Conclusions In this cohort of RA patients treated with abatacept (CTLA4Ig), low levels of IL-17 producing CD4⁺ T cells at baseline are associated with a better response to abatacept at 6 months. This novel finding (validation to a larger cohort in progress) may be used as an early biomarker to predict clinical responses to abatacept.

References

1. . McInnes, et al. The Lancet 2017.

2. . Wing, et al. Science 2008.

3. . Smolen, et al. Arthritis Res Ther 2015.

Acknowledgements Project funded by BMS (Investigator initiated study, BMS PROTOCOL NUMBER: 2014-ORE-0033), “Pancretia” health organization.