Although the first written descriptions of gout date back over 4000 years, it wasn’t until the mid nineteenth century that excess uric acid in the blood leading to needle-like urate deposits in joint spaces was recognised to be the cause of this painful condition. Nowadays, gout is the most common cause of inflammatory joint disease in older men, most commonly affecting men between the ages of 30 and 60. Uric acid is the end product of purine metabolism and most current treatments for gout inhibit xanthine oxidase, the enzyme responsible for oxidising xanthine to uric acid. On June 16th, Savient Pharmaceuticals announced that an FDA advisory committee had recommended that Krystexxa™ (pegloticase), a PEGylated form of recombinant porcine uricase, be granted marketing approval by the FDA for the treatment of chronic refractory gout.
Although uricase (urate oxidase) is present in many species, the gene is non-functional in humans so that uric acid is the endpoint of purine catabolism. Most other non-primates are able to convert uric acid to the more soluble allantoin, which is more easily excreted by the kidneys. A recombinant uricase, Elitek® (rasburicase) is already used to treat some patients undergoing cancer chemotherapy where tumour lysis is expected to lead to elevated levels of plasma uric acid.
NF-κB is a transcription factor that plays a key role in regulating cellular responses to stimuli such as stress and bacterial and viral infections. In un-stimulated cells, NF-κB dimers are sequestered in the cytoplasm by inhibitors known as IκBs (inhibitors of κB) which mask the nuclear localization signals of NF-κB. When the cell is stimulated, IκB proteins are degraded and the NF-κB complex is free to enter the nucleus where it can activate gene expression. The activation of particular genes by NF-κB then leads to a physiological response such as inflammation, an immune response, cell survival or cell proliferation. Once in the nucleus, NF-κB also turns on expression of IκBs, thus forming a feedback loop which regulates activity. Inappropriately regulated NF-κB has been linked to many different types of tumour as well as to inflammatory diseases.
It has been estimated that there are ten times as many bacterial cells as human cells in the body, with the vast majority of bacteria living in the intestine. Around 500 bacterial species are present in the normal human gut and generally provide a beneficial service, synthesizing vitamins such as folic acid, vitamin K and biotin, fermenting complex carbohydrates, and converting lactose to lactic acid. The presence of such bacterial colonies also inhibits the growth of potentially pathogenic bacteria. The microorganisms which populate the gut, termed the commensal microbiotica, are also actively involved in immune regulation and homeostasis and the composition of the microbiota has been suggested to influence susceptibility to inflammatory bowel diseases.