Background/Purpose: We reported that human T-lymphotropic virus type 1 (HTLV-1) positive patients with rheumatoid arthritis (RA) had higher inflammation and greater resistance to anti-TNF treatment than HTLV-1 negative patients. The levels of plasma IL-6 and CCL20 in HTLV-1 positive RA patients was significantly higher than in HTLV-1 negative patients. The objectives of this present study are to investigate the efficacy and safety of anti-IL-6 receptor antibody, tocilizumab (TCZ) treatment to HTLV-1 positive RA who were who were not responsive to anti-TNF therapies. In addition, we investigated whether HTLV-I infected cells modulates the expression of cytokine, chemokine, and matrix metalloproteinase in RA synovial fibroblast (RASF) in vitro.

Methods: We identified 5 of 6 HTLV-1 positive RA patients, who were not responsive to anti-TNF therapies, were administered TCZ treatment as their secondary biologics in our biologics cohort study. Therapeutic response at 3 months after beginning of treatment with TCZ was evaluated using EULAR response criteria. We also analyzed the changing of C-reactive protein (CRP), erythrosedimentation rate (ESR), disease activity score in 28 joints (DAS28) and clinical disease activity score (CDAI). As secondary endpoints, discontinuation rate of TCZ treatment and safety, especially the development of adult T-cell leukemia (ATL), were evaluated over a one-year period. HTLV-1 infected (MT2 or Hut102) or non-infected (Jurkat) cell-lines were co-cultured with RASF for 48h. To avoid direct-interaction between these cells, we setup transwell co-culture system using inserts with 0.4um pore membrane. The levels of 25 cytokines in cell culture medium were measured using multiplex cytokine assay (Luminex, Millipore). The level of soluble IL-6 receptor (sIL-6R) in culture medium was measured using ELISA. The phosphorylation of NF-kB p65 in RASF co-cultured with HTLV-1 infected or non-infected cells were determined by immune blotting. The expression of IL-6, CCL20, VEGF, and MMP1 mRNA in RASF was measured using real-time quantitative PCR.

Results: According to EULAR response criteria, the rate of good, moderate and no response after treatment with TCZ in HTLV-1 positive RA patients was 60, 40, and 0%, respectively. The rate of low disease activity was 60 %. The levels of CRP, ESR, DAS28, and CDAI were significantly decreased after treatment with TCZ. The efficacy of TCZ treatment sustained for at least one-year period. During the one-year observation period, no patients developed ATL. The protein levels of IL-6, CCL20, IFN-γ and sIL-6R in mono-culture medium of HTLV-1 infected cell lines was higher than in that of Jurkat cell. The phosphorylation of NF-kB p65 was increased in RASF co-cultured with HTLV-1 positive cells. The expression of IL-6, CCL20, VEGF and MMP1 mRNA increased in RASF co-cultured with HTLV-1 infected cells, but not with Jurkat cell.

Conclusion: TCZ improved response to therapy in HTLV-1 positive RA who were who were refractory to anti-TNF therapies. In vitro study showed that HTLV-1 infected cells induced the expression of IL-6, CCL20, VEGF and MMP in RASF. Taken together, these results suggested that IL-6 may play an important role in the pathogenesis of HTLV-1 positive RA patients.

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-6-may-have-an-important-role-in-the-resistance-to-anti-tnf-therapies-of-human-t-lymphotropic-virus-type-1-htlv-1-positive-rheumatoid-arthritis-ra-patients-htlv-1-infected-cells-activate-the-in/