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Yoshiya Tanaka,1 Kana Hoshino-Negishi,2 Yoshikazu Kuboi,2 Fumitoshi Tago,3 Nobuyuki Yasuda,2 Toshio Imai2 1First Department of Internal Medicine, University of Occupational and Environmental Health, Fukuoka, Japan; 2 KAN Research Institute Inc, Hyogo, Japan; 3Eisai Co. Ltd., Tokyo, JapanCorrespondence: Yoshiya TanakaFirst Department of Internal Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahata-Nishi, Kitakyushu, Fukuoka 807-8555, JapanTel +81-93-603-1611Fax +81-93-691-9334Email tanaka@med.uoeh-u.ac.jpAbstract: Rheumatoid arthritis (RA) is an autoimmune disorder that affects joints and is characterized by synovial hyperplasia and bone erosion associated with neovascularization and infiltration of proinflammatory cells. The introduction of biological disease-modifying anti-rheumatic drugs has dramatically changed the treatment of RA over the last 20 years. However, fewer than 50% of RA patients enter remission, and 10– 15% are treatment refractory. There is currently no cure for RA. Fractalkine (FKN, also known as CX3CL1) is a cell membrane-bound chemokine that can be induced on activated vascular endothelial cells. FKN has dual functions as a cell adhesion molecule and a chemoattractant. FKN binds specifically to the chemokine receptor CX3CR1, which is selectively expressed on subsets of immune cells such as patrolling monocytes and killer lymphocytes. The FKN–CX3CR1 axis is thought to play important roles in the initiation of the inflammatory cascade and can contribute to exacerbation of tissue injury in inflammatory diseases. Accordingly, studies in animal models have shown that inhibition of the FKN–CX3CR1 axis not only improves rheumatic diseases but also reduces associated complications, such as pulmonary fibrosis and cardiovascular disease. Recently, a humanized anti-FKN monoclonal antibody, E6011, showed promising efficacy with a dose-dependent clinical response and favorable safety profile in a Phase 2 clinical trial in patients with RA (NCT02960438). Taken together, the preclinical and clinical results suggest that E6011 may represent a new therapeutic approach for rheumatic diseases by suppressing a major contributor to inflammation and mitigating concomitant cardiovascular and fibrotic diseases. In this review, we describe the role of the FKN–CX3CR1 axis in rheumatic diseases and the therapeutic potential of anti-FKN monoclonal antibodies to fulfill unmet clinical needs.Keywords: fractalkine, CX3CR1, humanized anti-fractalkine monoclonal antibody (E6011), CD16+ monocyte, rheumatic diseases