Although several therapeutic options exist for treating rheumatoid arthritis (RA), not even the current gold standard therapies can reliably induce long-term, drug-free remission. Owing to the complex pathogenic processes involved in RA, combination therapies are being developed to target multiple pathways or cytokines at once.

Credit: Springer Nature Limited

In a new study, one such combination therapy has shown promise in inducing long-term remission in mice with collagen-induced arthritis (CIA). “Given the high costs of biologic therapies and potential for adverse events, we became interested in the therapeutic potential of small molecular weight modulators of TNF receptor signalling,” explains corresponding author Richard Williams. “We subsequently started to investigate inhibitors of cellular inhibitor of apoptosis proteins (cIAPs), which have a fundamental role in NF-κB pathway activation by TNF.”

The cIAP1 and cIAP2 antagonist GT13072 belongs to a class of inhibitors known as SMAC mimetics that are currently in phase I testing for the treatment of cancer. The researchers used GT13072 to treat mice with CIA and observed a large and rapid decrease in disease severity. Intriguingly, mice treated with GT13072 had reduced numbers of IL-17+ T cells compared with mice treated with a structurally related inactive compound. “A more detailed look into the mechanism of action of GT13072 revealed that it decreased NFATc1 expression in human T cells, which is a known regulator of IL-17A expression,” says first author Joanna Kawalkowska.

As inhibition of TNF can cause an increase in IL-17+ cells in patients with RA, the researchers decided to counter this effect by combining the TNF inhibitor etanercept with GT13072 to treat mice with CIA. Combination therapy had an additive effect on reducing disease severity in these mice and also prevented relapse for longer than treatment with either therapy alone.

combination therapy had an additive effect on reducing disease severity

“Perhaps the most important finding from this study was the long-term therapeutic effect of combination therapy, accompanied by an expansion of regulatory T cells,” concludes Williams. “Our objective is to translate these findings into the clinic and to initiate experimental medicine trials in patients with inflammatory diseases.”