title: Sustained elevation of interleukin-33 in sera and synovial fluids from patients with rheumatoid arthritis non-responsive to anti-tumor necrosis factor: possible association with persistent IL-1β signaling and a poor clinical response.
abstract: Although TNF inhibitors have dramatically improved the outcome of patients with rheumatoid arthritis, 30-40% of patients do not respond well to them and treatment needs to be changed. In an effort to discriminate good and poor responders, we focused on the change in serum and synovial fluid levels of interleukin (IL-) 33 before and after treatment with TNF inhibitors. They were also measured in synovial fluids from 17 TNF inhibitor-naïve patients, and fibroblast-like synoviocytes (FLS) in-culture from 6 patients and correlated with various pro-inflammatory cytokines. Serum levels of IL-33 at 6 months after treatment decreased significantly in responders, while they did not change in non-responders. Synovial fluid levels of IL-33 in 6 patients under treatment with TNF inhibitors stayed high in 3 who were refractory and slightly elevated in 2 moderate responders, while they were undetectable in one patient under remission. Among inflammatory cytokines measured in 17 synovial fluids from TNF inhibitor-naïve patients, levels of IL-33 showed a significant positive correlation only to those of IL-1β. IL-1β increased IL-33 expression markedly in FLS in vitro, compared to TNF-α. IL-1β might be inducing RA inflammation through producing pro-inflammatory IL-33 in TNF inhibitor-hypo-responders. Sustained elevation of serum and/or synovial levels of IL-33 may account for a poor response to TNF inhibitors, although how TNF inhibitors affect the level of IL-33 remains to be elucidated.
authors: Division of Rheumatology and Clinical Immunology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. yasushim@jichi.ac.jp
authors: Yasushi
authors: Y
authors: Matsuyama
authors: Hitoaki
authors: H
authors: Okazaki
authors: Motoaki
authors: M
authors: Hoshino
authors: Sachiko
authors: S
authors: Onishi
authors: Yasuyuki
authors: Y
authors: Kamata
authors: Katsuya
authors: K
authors: Nagatani
authors: Takao
authors: T
authors: Nagashima
authors: Masahiro
authors: M
authors: Iwamoto
authors: Taku
authors: T
authors: Yoshio
authors: Hiromi
authors: H
authors: Ohto-Ozaki
authors: Hiroyuki
authors: H
authors: Tamemoto
authors: Mayumi
authors: M
authors: Komine
authors: Hitoshi
authors: H
authors: Sekiya
authors: Shin-Ichi
authors: S
authors: Tominaga
authors: Seiji
authors: S
authors: Minota
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D000067596:Interleukin-33; D007378:Interleukins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D007564:Japan; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D013582:Synovial Fluid / Q000276:immunology*; D013997:Time Factors; D017211:Treatment Failure; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D018501:Antirheumatic Agents; D015415:Biomarkers; C506536:IL33 protein, human; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D000067596:Interleukin-33; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha