Rheumatoid Arthritis (RA) is a challenging autoimmune disease affecting millions worldwide. A 1992 clinical trial found that the asthma drug Zileuton alleviated RA symptoms, but the promising results did not lead to FDA approval. A recent paper in Science Signaling could reinvigorate efforts for FDA approval by identifying the mechanism behind Zileuton's effects on RA.
RA involves the immune system attacking the body's own tissues, with a key aspect being the inflammation of the synovium, the soft tissue lining the spaces around joints and tendons. The paper's findings shed light on a previously overlooked aspect of the disease's pathogenesis by delving into the role of pyroptosis—an inflammatory type of programmed cell death—in RA progression.
First, the study identified pyroptosis of CD4+ T cells in the blood as a "major effector cells of abnormal immunity in patients with RA." This cell death process releases inflammatory signals, exacerbating synovitis.
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Second, a transcriptional analysis of T cells from RA patients revealed over 50 with altered expression in RA CD4+ T cells, including the upregulation of the gene for an enzyme called arachidonate 5-lipoxygenase (ALOX5). Mapping the cascade of molecular events associated with ALOX5, the researchers detailed precisely how the enzyme enacts its pyroptotic effects.
Third, the study identified ALOX5 as a significant factor in CD4+ T cell pyroptosis, with high levels of ALOX5 associated with more severe RA symptoms. In patient populations, low levels of ALOX5-containing T cells were associated with disease remission.
Finally, treating a humanized mouse model of RA with Zileuton inhibited ALOX5, reducing CD4+ T cell pyroptosis, inflammation, and synovial inflammation.
There's little to no evidence why Zileuton's asthma applications took priority over further testing and FDA approval for RA. The findings of this study likely explain the pharmacological effects of Zileuton on RA back in 1992 and suggest that other ALOX5-associated proteins are potential therapeutic targets for managing this autoimmune condition.
Sources: Journal of Rheumatology, CDC, Science Signaling