51 - T-Cell-Related Cytokines Are Inhibited in Response to Tocilizumab in Patients with Rheumatoid Arthritis in Contrast with TNF-Inhibitor

Sunday, November 6, 2011: 9:00 AM-6:00 PM
Hall F2 - Poster Hall (McCormick Place West)
Jiro Yamana1, Mitsuyoshi Iwahashi2, Motoaki Kim1, Rie Sasaki1, Keisuke Kobayashi1, Seizo Yamana1, Yusuke Sasaki3, Yasushi Shimonaka3 and Masahiko Mihara4, 1Higashi-hiroshima memorial Hospital, Hiroshima, Japan, 2Higashi-Hiroshima Memorial Hospital, Higashi-hiroshima, Japan, 3Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan, 4Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan
Presentation Number: 51

Background/Purpose: Tocilizumab (TCZ), a humanized monoclonal antibody to the interleukin-6 (IL-6) receptor, inhibits the binding of IL-6 to its receptor, preventing IL-6 signaling.  However, the correlation between cytokine profiles and disease activity after TCZ administration in rheumatoid arthritis (RA) has not been clarified. We measured serum concentrations of cytokines in patients received TCZ to identify the mechanisms and predictors of TCZ efficacy in comparison with tumor necrosis factor (TNF) inhibitor.

Method: In 42 RA patients (27 in the TCZ group, 15 in the TNF-inhibitor group) , serum concentrations of IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12(p70), IL-13, IL-17, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage (GM)-CSF, interferon (INF) g, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1β, TNFα, chemokine (C-C motif) ligand (CCL)-20, IL-23 and TNF-like weak inducer of apoptosis (TWEAK) before treatment (M0) and after 6 months of treatment (M6) were measured by the multiplex method and ELISA. Clinical response was evaluated with disease activity score 28 using the C-reactive protein (DAS28-CRP) and European League against Rheumatism (EULAR) response criteria.

Result: DAS28-CRP was 4.7 ± 0.9 (mean ± SD) in the TCZ group and 5.1 ± 1.3 in the TNF-inhibitor group (p=0.16) at M0. The ratio of good responders / moderate responders / no responders at M6 was 16/9/2 in the TCZ group and 4/7/4 in the TNF-inhibitor group, respectively. Analysis of the cytokine profiles at M0 and M6 in good responders or moderate responders revealed that T-cell-related cytokines were inhibited mainly in the TCZ group, while chemokines were inhibited mainly in the TNF-inhibitor group (Table). When the cytokines that decreased to less than 40% at M6 were examined in good responders (TCZ group: 16, TNF-inhibitor group: 4), this trend was more pronounced in both groups (Table). Interestingly, the results of a univariate logistic regression analysis showed that M0 cytokines tended to be higher in good responders than in moderate responders.

Conclusion: Whereas TNF-inhibitor inhibits chemokine type cytokines and might reduce infiltration of inflammatory cells, TCZ inhibits T-cell-related cytokines and might normalize the immunological abnormality. Therefore, it is possible that TCZ can induce a deeper remission than TNF-inhibitors. In patients with high T-cell-related cytokine values before treatment, good response can be expected with TCZ. 

Difference between TCZ and TNF inhibitor in inhibition of cytokines
TCZ group TNF-inhibitor group
Significant inhibition at M6 IL-2, IL-7, IL-8, IL-12, GM-CSF, TNF IL-6, IL-8, MIP-1β, CCL-20
Among good responders, decrease to  ≤40% at M6 IL-2, IL-7, IL-10, IL-12, GM-CSF, IFNγ IL-6, IL-12, CCL-20
* IL-4, IL-5, IL-13, IL-17 and IL-23 were undetectable in more than 50% of RA patients at M0, so they were excluded from the analysis.

Keywords: tocilizumab

Disclosure: J. Yamana, None; M. Iwahashi, None; M. Kim, None; R. Sasaki, None; K. Kobayashi, None; S. Yamana, None; Y. Sasaki, Chugai Pharmaceutical, 3 ; Y. Shimonaka, Chugai Pharmaceutical, 3 ; M. Mihara, Chugai Pharmaceutical, 3 .