Background/Purpose: Abatacept (ABT) works through a different mechanism of action from TNF inhibitors in the treatment of rheumatoid arthritis (RA). ABT decreases T cell responses by limiting CD28 mediated signaling that is required for T cell activation and differentiation. However, little is known about T cell populations targeted by ABT. We investigated the relevance of the phenotype of CD4⁺ helper T cells to disease activity in patients with RA and responsiveness to treatment, elucidating targets to ABT.

Methods: Heparinized whole blood samples were obtained from 19 patients with RA and 15 healthy donors (HD). All patients were treated with ABT at baseline, week 2 and every 4 weeks, and blood samples were taken at baseline and week 24 after treatment. The phenotype of T cells was determined by flow cytometry and the results were correlated with the clinical disease activity with simplified disease activity index (SDAI), disease activity score based on 28 joints and Erythrocyte Sedimentation Rate (DAS28 (ESR)), anti- cyclic citrullinated peptide (CCP) antibody and rheumatoid factor (RF).

Results: The proportion of CD28^– cells among CD4⁺ cells increased in RA, compared to HD (p=0.04). Baseline levels of CD28 on CD4⁺ cells have positively correlated with DAS28 (p=0.00) and SDAI (p=0.03) at baseline as well as‡™DAS28 (p=0.0115) and ‡™SDAI (p=0.0574) in response to ABT for 24 weeks. By contrast, baseline proportion of CD4⁺CD28^– cells was higher in patients who failed to achieve a remission at 24 week after treatment. The proportion of CD4⁺ CXCR5⁺ Tfh (p=0.00) and CD4⁺CXCR3⁺ Th1 (p=0.08) cells increased in RA compared to HD. Those cells also expressed active surface markers such as CD38. CD4⁺CD28⁺ cells consisted of activated Tfh and Th1 in naïve and central memory phase: the proportion of Tfh cells increased in anti-CCP antibody-positive patients (p=0.05), whereas that of Th1 cells tended to be correlated with disease activity (p=0.07). CD4⁺CD28^– cells consisted of Th1 in effector memory phase, showing no correlation to disease activity and antibody production. Finally, the proportion of Tfh cells was significantly decreased after ABT treatment (p=0.03), but those of Th1 cells was not changed (p=0.26).

Conclusion: These results imply that CD4⁺CD28⁺ cells, which consist of Tfh cells in central memory phase associated with production of anti-CCP, are target of ABT, whereas CD4⁺CD28^– cells, which consist of terminally differentiated Th1 cells, might be associated with refractoriness to ABT therapy. The evaluation of T cell phenotype may serve to predict to the response to ABT therapy in advance in patients with RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-differential-role-of-t-helper-cells-in-the-pathogenesis-and-responsiveness-to-abatacept-therapy-in-rheumatoid-arthritis/