Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid A and interleukin-6 during treatment for rheumatoid arthritis

Abstract

The Janus kinase inhibitor tofacitinib is currently being investigated as a disease-modifying agent in rheumatoid arthritis (RA). We investigated the in-vivo effects of tofacitinib treatment for 4 weeks on elevated circulating acute-phase serum amyloid (SAA) levels in 14 Japanese patients with RA. SAA levels fell from 110·5 ± 118·5 μg/ml (mean ± standard deviation) at treatment initiation to 15·3 ± 13·3 μg/ml after 4 weeks treatment with tofacitinib. The reduction in SAA levels was greater in patients receiving tofacitinib plus methotrexate compared with those receiving tofacitinib monotherapy. Tofacitinib was also associated with reduced serum interleukin (IL)-6, but had no effect on serum levels of soluble IL-6 receptor. Patients were divided into groups with adequate (normalization) and inadequate SAA responses (without normalization). Serum IL-6 levels were reduced more in the group with adequate SAA response compared with those with inadequate SAA response. These results suggest that tofacitinib down-regulates the proinflammatory cytokine, IL-6, accompanied by reduced serum SAA levels in patients with active RA. The ability to regulate elevated serum IL-6 and SAA levels may explain the anti-inflammatory activity of tofacitinib.

Keywords: Janus kinase; interleukin-6; rheumatoid arthritis; serum amyloid A; tofacitinib.

Fig. 1

The serum levels of acute-phase serum amyloid (SAA) from rheumatoid arthritis (RA) patients receiving tofacitinib treatment. SAA was measured before and at 4 weeks after tofacitinib treatment. There was a significant difference between the SAA levels before and at 4 weeks.

Fig. 2

The serum levels of acute-phase serum amyloid (SAA) from rheumatoid arthritis (RA) patients receiving methotrexate (MTX) plus tofacitinib or tofacitinib alone. SAA was measured before and at 4 weeks after tofacitinib treatment.

Fig. 3

The serum levels of interleukin (IL)-6 from rheumatoid arthritis (RA) patients receiving tofacitinib treatment. IL-6 was measured before and at 4 weeks after tofacitinib treatment. There was a significant difference between the IL-6 levels before and at 4 weeks.

Fig. 4

The serum levels of interleukin (IL)-6 from rheumatoid arthritis (RA) patients with or without acute-phase serum amyloid (SAA) normalization. RA patients receiving tofacitinib were divided into patients with an adequate decline in SAA (normalization; <8 μg/ml) and patients with an inadequate SAA decline (without normalization, ≥8 μg/ml) at 4 weeks. SAA was measured before and at 4 weeks after tofacitinib treatment in both patient groups. There was a significant difference between the IL-6 levels before and at 4 weeks in the patients with SAA normalization.

Fig. 5

DAS28 [C-reactive protein (CRP)] in from rheumatoid arthritis (RA) patients with or without acute-phase serum amyloid (SAA) normalization. RA patients receiving tofacitinib were divided into patients with an adequate decline in SAA (normalization; <8 ug/ml) and patients with an inadequate SAA decline (without normalization, ≥8 μg/ml) at 4 weeks. DAS28 (CRP) was measured before and at 12 weeks after tofacitinib treatment in both patient groups. There was a significant difference between DAS28 (CRP) before and at 12 weeks in the patients with SAA normalization.

Fig. 6

The serum levels of soluble interleukin (sIL)-6R from rheumatoid arthritis (RA) patients receiving tofacitinib treatment. sIL-6 receptor (sIL-6R) was measured before and at 4 weeks after tofacitinib treatment. There was no significant difference between the sIL-6R levels before and at 4 weeks.