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.