Research from Dr Richard Williams' group at the Kennedy Institute reveals a potential new approach to limit inflammation in rheumatoid arthritis and increase the likelihood of drug-free disease remission.
Anti-TNF drugs have dramatically improved the lives of many patients living with rheumatoid arthritis. Not all patients respond to therapy however, and most relapse if treatment is withdrawn. The new research published in Scientific Advances shows that targeting molecules called cIAPs in combination with a TNF inhibitor effectively treats inflammatory arthritis in animals, with sustained benefit even after treatment ends.
Speaking of the research Richard says, "Increasingly, patients with rheumatoid arthritis and other autoimmune diseases are seeking treatments that lead to sustained drug-free disease remission and this objective will most likely be achieved by early intervention and the use of combination therapy."
"We became interested in cIAPs because they control the biological pathways activated by TNF, a driver of inflammation in rheumatoid arthritis. Unexpectedly, we found that blocking cIAP1 and cIAP2 reduces the activity of some white blood cells which are known to promote inflammation in tissues".
Dr Joanna Kawalkowska and co-workers in Richard's team showed that the inhibitor of these cIAPs, a molecule by the name of GT13072, reduced the severity of disease in mice when administered continuously. However, when they combined GT13072 with the TNF inhibitor, Etanercept, the reduction in disease was sustained after treatment was stopped.
A more detailed look into the mechanism revealed that GT13072 decreased the amount of a protein known to regulate Th17 cell differentiation. This was accompanied by a marked increase in the joints of regulatory T cells, that promote healthy immune responses.
"Resetting the balance between Th17 cells and regulatory T cells may underlie the long-term benefits of GT13072 when combined with Etanercept", explains Richard.
The research suggests that inhibitors of cIAPs, which are already in clinical development for cancer, may also be suitable for management of rheumatoid arthritis and other autoimmune diseases