IL1Ra Anakinra

Pharmacology and Mechanism of Action

IL-1 is another key proinflammatory cytokine in the pathogenesis of RA. It is produced by a variety of cells including monocytes, macrophages, and synoviocytes. There are several forms of IL-1, membrane-associated IL-1 a and soluble IL-1^. Unlike TNF, activation of the IL-1 pathway also leads to release of its endogenous inhibitor IL-1Ra. Although levels of IL-1Ra are increased in RA patients compared with the healthy controls, the relative increase in IL-1Ra is insufficient to prevent signalling of IL-1 (6,93). Anakinra is a recombinant human IL-1Ra and binds IL-1R, thereby preventing binding of native IL-1. IL-1Ra has a short half-life and is therefore administered daily by a subcutaneous injection. In clinical trials, it has been shown to be efficacious for both clinical improvement and reducing radiological progression of RA (93,94).

Genetics of IL-1

No studies to date have evaluated genetic predictors of response to treatment with IL-1Ra. The genes for IL-1 and IL-1Ra are found on the long arm of chromosome 2. In one study, a polymorphism within the IL-1^ promoter sequence (at position 511) was overrepresented in an RA population who had required joint surgery, compared with both patients who had not required surgery and healthy controls (95). This polymorphism may therefore be a marker of RA severity. However, Huang et al. (96) looked at the same polymorphism in a Taiwanese population and did not find an increased allele frequency in the RA group compared with the controls. These and other gene polymorphisms in the IL-1 family may be hypothesized to influence responses to IL-1Ra therapy and clearly require further evaluation.

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