1267 - Tofacitinib Reduces Interferon-γ and Interleukin-17 Production From CD4+ T Cells in Patients with Rheumatoid Arthritis

Monday, November 7, 2011: 9:00 AM-6:00 PM
Hall F2 - Poster Hall (McCormick Place West)
Satoshi Kubo, Kunihiro Yamaoka, Koshiro Sonomoto, Keisuke Maeshima, Shintaro Hirata, Kazuhisa Nakano, Norifumi Sawamukai, Masao Nawata, Shigeru Iwata, Kazuyoshi Saito and Yoshiya Tanaka, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
Presentation Number: 1267

Background/Purpose: 

Tofacitinib, a Janus kinase (JAK) inhibitor, has gathered attention in treatment of rheumatoid arthritis (RA), revealing the prompt clinical effects in randomized clinical trials. However, its mode of action remains uncertain, particularly when administered to RA patients. Therefore, we collected CD4+ T cells from RA patients treated with tofacitinib, and investigated the cytokine prolife from T cells in vitro and its relevance to clinical efficacy.

Method: 

Patients who met the ACR criteria for RA and participated in the tofacitinib clinical trials and continued medication up to 52 weeks in our department were eligible. After the double blind period (12- or 24-weeks), during which patients were randomized to receive different doses of tofacitinib or placebo, all patients were treated with tofacitinib 5 mg or 10 mg BID open-label. CD4+ T cells from blood were collected by magnetic selection at 0 and 52-weeks and cultured under the stimulation with anti-CD3 and anti-CD28 antibodies for 3 days. Serum levels of IFN-γ and IL-17 in collected supernatants were measured by ELISA.

Result: 

(1) Patient background: 30 patients were assigned, mean age; 53.8 years, mean disease duration; 82.2 months, methotrexate was administered in 23 patients and the median dose was 9.2 mg/week, oral corticosteroids were administered in 7 patients and the median dose was 6.0 mg/day. At baseline, patients had a high degree of disease activity: - SDAI 37.6, DAS28 (ESR) 6.3, HAQ 1.8, CRP 20.3 mg/l, ESR 50.7 mm/h, MMP-3 229.4ng/ml, RF 208.0U/ml.

(2) The mean disease activity score was SDAI=7.7 and DAS28=3.1 at 52-weeks, which was significantly lower than that at baseline (P<0.05) and 73% achieved low disease activity (SDAI < 11). HAQ was 0.7 at 52-weeks and 46% achieved HAQ-remission (HAQ<=0.5).

(3) Production of IFN-γ from CD4+ T cells at 52-weeks (1124.8 pg/ml) was significantly reduced, compared to that at baseline (1563.8 pg/ml) (P<0.05). Similar findings were noted in IL-17 production. IL-17 production at 52-weeks (1021.2 pg/ml) significantly decreased from that at baseline (1820.5 pg/ml) (P<0.05).

(4) There was no statistically significant correlation between the reduction of IFN-γ and IL-17 production from CD4+ T cells and improvement of clinical disease features including SDAI, CRP, ESR, MMP-3 and RF.

Conclusion: 

Tofacitinib acts on CD4+ T cells and suppress production of IFN-γ and IL-17 after 52 weeks of administration in patients with RA, suggesting the inhibitory effect on Th1 and Th17 differentiation. However, the reduction of cytokine production did not correlate with the clinical efficacy suggesting that tofacitinib acts not only on CD4+ T cells but also on other immune cells (such as dendritic cells, synovial fibroblast, and B cells) which may have direct or indirect connection with clinical efficacy.


Keywords: Janus kinase (JAK), T cells, cytokines and rheumatoid arthritis (RA)

Disclosure: S. Kubo, None; K. Yamaoka, None; K. Sonomoto, None; K. Maeshima, None; S. Hirata, None; K. Nakano, None; N. Sawamukai, None; M. Nawata, None; S. Iwata, None; K. Saito, None; Y. Tanaka, Abbott Japan, Astellas Pharma, Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Janssen Pharmaceutical KK, Mitsubishi Tanabe Pharma, Merck & Co. Inc, Pfizer Japan Inc., and Takeda Pharmaceutical Co. Ltd., 2, Abbott Japan, Astellas Pharma, Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Janssen Pharmaceutical KK, Mitsubishi Tanabe Pharma, Merck & Co. Inc, Pfizer Japan Inc., and Takeda Pharmaceutical Co. Ltd., 5, Abbott Japan, Astellas Pharma, Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Janssen Pharmaceutical KK, Mitsubishi Tanabe Pharma, Merck & Co. Inc, Pfizer Japan Inc., and Takeda Pharmaceutical Co. Ltd., 8 .