Rheumatoid arthritis (RA) is a long-term chronic autoimmune disease in which the body’s own immune system mistakenly targets the lining of the joints. Patients with RA suffer from pain, stiffness, and joint swelling, and the disease is often accompanied by severe underlying joint damage which may result in disability. In addition, many patients will have one or more comorbidities, including cardiovascular disease, interstitial lung disease, osteoporosis, cancer, and depression.
As there is presently no cure for RA, most treatments aim to relieve pain and reduce swelling mainly by targeting pathological inflammation. One class of biologic drugs, which targets a pro-inflammatory protein called tumor necrosis factor (TNF), has shown to be effective in most RA patients. Indeed, prospects for RA patients have improved dramatically since the advent of TNF inhibitors and have raised expectations of the possibility of a cure. Unfortunately, not all RA patients will respond adequately to TNF inhibitors, and most will relapse when treatment is withdrawn.
Thus, continued efforts to develop drugs capable of providing long-term remission of RA are required. Currently, less than a quarter of patients who receive the gold-standard treatment of anti-TNF plus methotrexate achieve remission and, in most cases, relapse when treatment is withdrawn. Furthermore, many patients who initially respond well lose their response over time.
We previously showed in a mouse model of RA that treatment with TNF inhibitors causes a paradoxical increase in numbers of a subset of lymphocytes, known as Th17 cells, which are important drivers of inflammation and tissue damage. The same phenomenon has also been shown in a number of human studies. Thus, although anti-TNF therapy is very effective in suppressing inflammation, it fails to halt, and may actually exacerbate, the underlying pathogenic immune response. The findings also suggest that there could be an added benefit from combining a TNF inhibitor with an inhibitor of Th17 cells.
TNF acts by binding to specific cell surface receptors and, given the high costs of biologics and potential for adverse events, we became interested in the therapeutic potential of small molecular weight modulators of TNF receptor signaling. We subsequently started to investigate inhibitors of cellular inhibitor of apoptosis proteins (cIAPs), which play a fundamental role in NF-kB pathway activation by TNF. Our original hypothesis was, therefore, that cIAP inhibitors would alter the response of cells to TNF. However, we unexpectedly found that cIAP inhibitors had a profound inhibitory effect on human Th17 cells. We went on to assess the therapeutic effects of one cIAP inhibitor, GT13072 (kindly provided by Tetralogic Pharmaceuticals), in an animal model of RA.
Our study revealed that targeting cIAP1/2 in mice with arthritis leads to a significant reduction in the severity of the disease. These results also confirmed that levels of IL-17 (a product of Th17 cells) were significantly lower in mice that received the cIAP antagonist. A more detailed look into the mechanism of action of GT13072 revealed that it decreased in the levels in human T cells of NFATc1 in human T cells, a known regulator of Th17 differentiation.
We also studied the effect of GT13072 in combination with anti-TNF in the CIA model. Remarkably, we observed that combined treatment with GT13072 and a TNF inhibitor (etanercept), the mice showed no signs of disease and remained symptom-free after the withdrawal of both drugs. In the joints of mice that received combination therapy, we observed a significant decrease in Th17 cells and an increase in an immunosuppressive lymphocyte subset known as regulatory T cells. Notably, in vitro, we were able to confirm that targeting cIAP1/2 stopped the development of TH17 cells and their secretion of pro-inflammatory signals which alert other immune cells in the joint lining.
In summary, our results indicate that not only are cIAP1/2 novel targets in auto-immune diseases, but they also provide insight into the molecules and pathways controlling the balance between pro- and anti-inflammatory immune cell subtypes in these diseases. Inhibitors of cIAPs are in clinical development for cancer and these findings indicate their potential use in autoimmune disease. However, perhaps the most significant finding was the long-term therapeutic effect of combination therapy.
Increasingly, patients with RA and other autoimmune diseases are demanding treatments that lead to drug-free disease remission, and this is most likely to be achieved by early intervention and the use of combination therapy (in a similar manner to the current treatment of cancer). Hence, these findings have implications for future management of RA.
These findings are described in the article entitled cIAP1/2 inhibition synergizes with TNF inhibition in autoimmunity by down-regulating IL-17A and inducing Tregs, recently published in the journal Science Advances.
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