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.