Can RA drugs fill the treatment gap in OA?

With new therapies for osteoarthritis pain likely some way off, could repurposed drugs fill the treatment gap the meantime? We’ve spoken to Dr Fiona Watt from the UK’s Kennedy Institute of Rheumatology, NDORMS, University of Oxford about the trials that may very well answer this question.

In particular, Dr Watt and her fellow researchers are working on two large clinical trials looking at whether two established rheumatoid arthritis drugs, hydroxychloroquine and methotrexate, can improve pain in hand and knee OA, respectively.

The idea of borrowing treatments from the RA arena stems from increasing awareness that inflammation plays a role in OA, Dr Fiona Watt consultant rheumatologist and senior clinical research fellow at the Arthritis Research UK Centre for Osteoarthritis Pathogenesis at the Kennedy Institute told the limbic.

She says that while it’s still not clear whether inflammation in the traditional sense drives the disease, research shows that at a cellular level inflammatory pathways are activated.

“Also, clinical research has told us that we see a lot of synovial inflammation in the disease. There is still debate as to whether that’s a primary phenomenon or secondary thing, but it certainly seems to be associated with pain and a predictor of progression in the disease from MRI studies in the knee,” she explained.

“So this has brought about a dialogue as to what we’d consider to be anti-synovial treatments from rheumatoid and other inflammatory arthropathies.”

Inclusive and pragmatic trials

Dr Watt says the two multicentre randomised controlled trials, led by Professor Philip Conaghan at the University of Leeds and funded by Arthritis Research UK, have been designed to be quite inclusive and pragmatic.

The participants, who had OA pain that had not responded to current treatments, did not have to have evidence of inflammation to be included, so if the results are positive the treatments can be slotted into existing care reasonably well, she said.

“I think it’ll be very interesting to look at the results and whether phenotyping patients is important in terms of trial outcomes or whether we can have a pragmatic inclusive approach when it comes to these drugs,” she added.

Results from the first of the trials HERO (Hydroxychloroquine Effectiveness in Reducing Symptoms of hand OA) has been submitted in abstract form to the ACR meeting this November.

The PROMOTE (Pain Reduction with Oral Methotrexate in knee Osteoarthritis, a pragmatic phase III trial of Treatment Effectiveness) trial is still in recruitment in some sites.

Dr Watt thinks there may be other opportunities for repurposing other drugs for OA, such as bisphosphonates that have an effect on bone and could also have important effects on structure if not on symptoms in OA.

She sees repurposing as a pragmatic approach to the problem that there is a desperate need for new medical therapies for OA pain.

“There is a big treatment gap in terms of large joint OA where patients are either too young or too early in their disease process to consider joint replacement surgery.

There is a big push from patients and from researchers to identify drugs that could be useful now, not in 10 years time,” she said.

The search for novel targets

But that’s not to say the Kennedy Institute isn’t interested in cutting edge science as well. It has a large research program that is trying to better understand the mechanisms underlying OA to try to find novel targets for the disease.

Dr Watt says preclinical models have provided a lot of information about the processes that drive the progression of the disease, and importantly suggested that OA is potentially a drug-treatable condition.

Along with others, the Kennedy Institute has shown that nerve growth factor (NGF) appears to be one of the main molecules contributing to OA pain.

It is now in the early stages of conducting two randomised clinical trials of agents that inhibit the NGF pathway, in partnership with two commercial companies. Recruitment has begun for the first of these in knee OA.

It also has several studies underway following people at high risk of developing OA as a result of knee injury, investigating the molecular response within the joint at the time of injury to see whether this predicts outcome in terms of pain or disease over time.

Dr Watt says there is a lack of understanding as to why after injury some people resolve and don’t develop symptomatic OA, while others become symptomatic, develop pain and run on a trajectory that is progressive.

And until more is known about this it will be difficult to use preventative treatments at an earlier stage because of the risk of over treating. But in the future, predicting risk of progression would allow intervention at a much earlier stage in the disease process, both after joint trauma, and in early OA.

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