The CX3CL1/CX3CR1 Axis is a Sensitive Marker of the Response to Anti-Tumor Necrosis Factor Therapy in Patients with Rheumatoid Arthritis

Review Article


Tsuyoshi Kasama^1, Michihito Sato^1, Ryo Takahashi^1, Tsuyoshi Odai^1, Takeo Isozaki¹ and Kazuo Kobayashi²

Affiliations: ¹Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan and ²Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan

ABSTRACT

The tumor necrosis factor (TNF) antagonists (anti‐TNF biologics) infliximab (IFX), adalimumab (ADA), and etanercept (ETN) are commonly used worldwide for rheumatoid arthritis (RA), have produced clinical improvement in signs and symptoms, disability, and quality of life, and have significantly inhibited the progression of joint damage in early and long‐standing disease. However, although anti‐TNF biologics often induce rapid clinical improvement in patients with RA, 20–40% of RA patients show little or no clinical response. To maximize the clinical response to these agents, the mechanism underlying the variable response in individual patients must be understood; furthermore, a strategy is needed to predict responders and non‐responders. Recently, several reports have demonstrated that cytokines and chemokines seem to be important and sensitive mediators in RA patients treated with anti‐TNF biologics. We showed that serum CX3CL1 levels were decreased in response to IFX treatment, whereas there were no significant and uniform alterations after IFX treatment in other chemokines that have crucial roles in the pathogenesis of RA development. In addition, the most interesting result in the present study was that the lack of response in the active RA group despite treatment with IFX could be related to higher basal levels of CX3CL1 and its receptor, CX3CR1. In conclusion, the CX3CL1/CX3CR1 axis and other chemokine receptors, such as CCR3 and CCR5, in patients with active RA may be sensitive to anti‐TNF therapy. These results also suggest that basal serum CX3CL1 levels correlate with the responsiveness of RA patients to IFX therapy.

Keywords: anti-TNF therapy, chemokine, CX3CL1, CX3CR1, cytokine, fractalkine, infliximab, rheumatoid arthritis

Correspondence: Tsuyoshi Kasama, Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Tokyo, 142-8666, Japan. Tel: +81-33784-8942; Fax: +81-33784-8946; e-mail: tkasama@med.showa-u.ac.jp