Statins could be effective in relieving symptoms of rheumatoid arthritis
April 25, 2017
The inflammatory nature of rheumatoid arthritis puts sufferers at an increased risk of cardiovascular disease. Statins are well known for reducing vascular risk; Iain McInnes, Naveed Sattar, and colleagues from the Glasgow Royal Infirmary, University of Glasgow, UK, investigated whether statins would reduce inflammatory factors in patients with rheumatoid arthritis.
116 patients were randomly allocated either daily 40 mg atorvastatin or placebo in addition to therapy for rheumatoid arthritis. All patients were assessed after 6 months. Among patients given atorvastatin there was a small but statistically significant improvement in arthritis symptoms compared with those given placebo (assessment was done using a composite score for disease severity which included scores for swollen joints and pain scores).
The clinical implications of the study findings are discussed by Lars Klareskog and Anders Hamsten from the Karolinska Institute, Sweden, in an accompanying Commentary (p 2011). Dr Klareskog concludes: "Although of limited size and short-term, their findings support the use of atorvastatin, and presumably of other statins, to prevent cardiovascular disease in patients with rheumatoid arthritis. Needless to say, more work is needed to define the long-term effects on inflammatory diseases and cardiovascular co-morbidities, and to expand the basic understanding of how various statins affect the immune system".
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Cohen and his colleagues tested the ability of the 11 compounds to inhibit an MMP enzyme in a test tube. They also studied the strength of binding of each of the 11 compounds to a chemical model that they had designed to mimic the way the zinc is bound in the active site of the enzyme. The researchers found that the ability of the compounds to inhibit the enzyme increased as the strength of their binding to the model increased. This is what is expected if the inhibitor is working by binding to the active site of the enzyme, rather than some unknown mechanism.
There are actually 26 MMPs in the human body, so to avoid unwanted side effects, drugs need to be designed that target specific MMPs. Since the active site for each of these MMPs contains a zinc ion, the 11 inhibitors would not target just one MMP. Designing inhibitors that target a single type of MMP requires modifying the way the inhibitor binds to chemical groups of the enzyme unique to that enzyme. Modifying the inhibitors to make them target specific enzymes will be the researchers??™ next steps, but according to Cohen, there is a great deal of published work that will help them with this task. Computational chemistry can also help them now that they have figured out the tricky metal-binding part.
???Although the use of models in chemistry is very well established, we are among the first groups to aggressively use model chemistry as a part of drug design,??? says Cohen. ???So far, our work has been particularly well received in the community of MMP research.???
The other researchers that contributed to this work are David Puerta and Jana Lewis, graduate students in the Cohen lab. The study was supported by UCSD, a Chris and Warren Hellman Faculty Scholar award, and the American Heart Association.
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