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BackgroundRecent studies have shown that increased number of Th17 cells and decreased number of Treg cells in the peripheral blood contribute to ankylosing spondylitis (AS). However, current therapy for AS, including biological agents, immunosuppressant and glucocorticoid, can not correct the imbalance of Th17 and Regulatory T (Treg) cells in AS patients effectively. It has been reported that low dose IL-2 can selectively expand Treg cells and had a critical effect on homeostatic balance between the Th17 and Treg cells.ObjectivesThe study is to explore the effect of low dose IL-2 therapy on the balance of Treg and Th17 cells in patients with AS and observe the efficiency and side effects of the therapy.MethodsSeventeen patients, who met the 1984 modified New York criteria and had evidence of active inflammatory spondylitis (defined as Bath AS Disease Activity Index (BASDAI) score >4) despite of receiving standard therapy including glucocorticoid, immune-suppressants, biological agents or combination of them, were enrolled. These patients were not only given traditional treatment, but also injected subcutaneously low-dose IL-2 (50 WIU/day for 5 days). Clinical and laboratory indicators were compared before and after IL-2 treatment. The side effects were observed in the course of therapy.ResultsThe number of Treg cells significantly increased after the treatment by 1 week (22.58±12.80 vs. 73.46±33.79, p<0.001). At the same time, there was a significantly decrease in the ratio of Th17/Treg cells (0.67±0.70 vs. 0.32±0.33, p=0.068). Besides, Th17 cells were also increased (12.83±9.24 vs. 19.26±13.24, p=0.054). Clinical manifestations were improved after the combination treatment of IL-2 and traditional drugs, especially BASDAI was decreased (4.57±0.61 vs. 1.98±0.83, P<0.001). No obvious adverse reactions were observed.ConclusionsLow dose IL-2 therapy can restore and maintain the balance of Th17 and Treg cells in the active patients with AS. Manifestation improved after the combination therapy. The therapy is safe. Further research is needed to investigate long term benefits of low-dose IL-2 therapy.References Wright P, Utriainen L, Milling S. Dendritic cells and regulatory T cells in spondyloarthritis. Curr Opin Rheumatol. 2013; 25(4):440–7.Zambrano-Zaragoza JF, Agraz-Cibrian JM, González-Reyes C, et al. Ankylosing spondylitis: from cells to genes. Int J Inflam. 2013; 2013:501653.Klatzmann D, Abbas AK. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol. 2015;15(5):283–94.He J, Zhang X, Wei Y, et al. Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus. Nat Med. 2016;22(9):991–3. Disclosure of InterestNone declared

Objective Rheumatoid arthritis (RA) multidrug resistance is associated with P-glycoprotein (P-gp) overexpression. We investigated the effects of methotrexate (MTX) alone and combined with 4-hydroperoxycyclophosphamide (4-HC) on P-gp expression in fibroblast-like synoviocytes (FLSs) from patients with RA and examined the signaling pathway involved. Methods RA-FLSs were treated with MTX, MTX + 4-HC, AG490 + MTX, or AG490 + MTX + 4-HC for 72 h. Proliferation inhibition rates were determined by MTT assay; P-gp expression was measured by flow cytometry and real-time polymerase chain reaction (RT-PCR); JAK2 and STAT3 were measured by RT-PCR and cell-based ELISA to assess STAT3 signaling. Results MTX alone significantly induced P-gp expression and mRNA production in RA-FLSs. P-gp expression and mRNA levels were lower in the MTX + 4-HC group than in the MTX-alone group. In contrast to MTX, MTX + 4-HC reduced the STAT3 phosphorylation and downregulated JAK2 and STAT3 mRNA production. Inhibition of constitutively active STAT3 accompanied by 4-HC suppressed P-gp levels in RA-FLSs. The MTT assays revealed no significant differences in proliferation inhibition rates among groups. Conclusions The increased anti-P-gp effect of MTX + 4-HC versus MTX alone in RA-FLSs was mediated via inhibition of the JAK2/STAT3 pathway and may have helped reverse MDR in refractory RA patients with high-P-gp levels.