Retinoic acid metabolism blocking agents (RAMBAs) to treat hand osteoarthritis

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Hand osteoarthritis (OA) is a debilitating condition affecting over 2 million people in the UK that causes pain and swelling in the base of the thumb and small joints of the hands. The condition can affect people's independence, quality of life and ultimately, for some, the ability to work. Currently there is no cure available. The only available drugs used in hand OA are standard pain killers and steroid injections. What causes osteoarthritis remains poorly understood. However, we know that excessive loading of joints (through injury, or over loading), being female and having a family history of the condition are all strong risk factors for developing the disease. The condition arises when pathways typically associated with inflammation are switched on in joint tissues including the articular cartilage of the joint, the smooth lining on the ends of the bones, leading to tissue damage and pain. A gene has recently been linked to hand osteoarthritis which controls the production of retinoic acid (vitamin A) levels in tissues in the body. We have shown that joint injury causes levels of retinoic acid activity to fall in cartilage, and that the drug talarozole, a retinoic acid metabolism blocking agent (RAMBA) prevents that drop. We already knew that joint injury to cartilage in the laboratory switches on inflammation in the tissue, but have shown that the presence of a RAMBA at the time of cartilage injury prevents this increase in inflammation. In patients undergoing hand surgery who donated their waste tissue samples, we have shown that having at least one copy of this gene variant is quite common in hand OA (~75% of those with the condition) and that this variant is associated with lower levels of retinoic acid pathway activity and higher levels of inflammation in joint cartilage compared to those without this gene variant, further supporting an important role for this pathway in the disease. The drug used in our laboratory studies, talarozole has been used in clinical trials of psoriasis and appears safe and well tolerated, but has not made it to the clinic for other conditions. In this experimental medicine study we want to test in patients with hand OA whether talarozole when given by mouth can:1. get into OA joint cartilage 2. normalise levels of retinoic acid and its family members in joint cartilage3. reduce inflammation levels in joint cartilage 4. have any effect on levels of hand pain over a short duration To do this we will ask 44 patients who are undergoing base of thumb surgery for hand OA (an operation that removes the small bone at the base of the thumb, which is usually discarded) to take a drug before their surgery and then donate their surgical tissue sample so that we can measure the drug's effects. Those who agree to take part will be asked to take either talarozole for 14 days before their surgery or a sugar tablet that looks like talarozole, but does not contain active drug (placebo). Our main outcome will be to see if there is a difference in the gene message level of a key retinoic acid family member between those taking the active drug and those taking placebo. (We have identified this readout as reliable from our earlier studies). We will also look at a defined panel of inflammation genes and whether these are lower in those on the active drug. On the day of starting the drug, during the 14 days and on the day of surgery, we will also collect questionnaire information on hand pain and function. The study will run at a single hospital for 3 years, managed by doctors and researchers with a strong track record of research linking the clinic with the laboratory. It is hoped that if this study is successful, that a larger, longer trial testing whether a RAMBA could help pain and disease progression in hand OA could then be undertaken.