Background/Purpose:

Inhibition of interleukin 6 (IL-6) receptor with tocilizumab (TCZ) is effective for rheumatoid arthritis (RA). However, the effect of TCZ on lymphocytes remains poorly studied. We analyzed the effect of TCZ on proportion of B, T, natural killer (NK) and NK T (NKT) cells in patients with RA and healthy controls and cell type predictors of disease activity response (disease activity in 28 joints [DAS28]). Secondary objectives were association of NK cells and disease activity in patients with RA, effect of TCZ on NK-cell cytotoxicity and effect of anti-tumor necrosis factor (anti-TNF) therapy on NK-cells.

Methods: Included patients had to meet 2010 ACR/EULAR criteria, be receiving steroids with stable doses < 10 mg per day and not have received rituximab in the previous year. Healthy subjects were recruited. Patients with TCZ introduced at baseline were followed at 3 and 6 months. Different B and T cell subsets, NK and NKT were assessed by flow cytometer as well as perforin A and granzyme B to estimate NK-cell cytotoxicity.

Results:

We included 25 controls and 92 RA patients, including 20 requiring TCZ treatment and 15 requiring anti-TNF drugs. At baseline, patients with RA had significantly lower proportion of regulatory T cells (Tregs), as defined by CD4⁺CD25^hiCD127^lo, than controls (p=0.003), and the proportion of CD56^dimCD16⁺CD3^– NK cells was inversely correlated with DAS28. The proportion of Tregs was increased at 3 months but not 6 months. Baseline proportion of CD3^–CD56⁺ NK cells was inversely correlated with change in DAS28 score at 3 months, and the proportion was three-fold greater for patients with DAS28 < 2.6 (disease remission) at 3 months than other patients. Change in proportion of CD56^briCD16^– NK cells was linearly correlated with change in DAS28 at 3 months. The baseline proportion of NK cells did not predict change in disease activity at 3 months with anti-TNF therapy. Perforin content in NK cells was increased with TCZ treatment.

Conclusion: This study supports NK cell involvement in RA.  TCZ transiently increased the proportion of Tregs and increased perforin content in NK cells. NK cells at baseline could be a predictive factor of TCZ response if results are confirmed.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/high-levels-of-natural-killer-cells-are-associated-with-response-to-tocilizumab-in-patients-with-severe-rheumatoid-arthritis/