Rheumatoid arthritis

Profile: McInnes on pinpointing the molecular secrets of inflammatory arthritis

Rheumatologist and EULAR President Professor Iain McInnes talks to the limbic about his research centre’s work to generate an increased knowledge of inflammatory arthritis at the molecular level that he hopes will leave clinicians “spoilt for choice” when it comes to new treatments and diagnostics.

Since its launch in 2014, work carried out by teams at the UK’s Research into Inflammatory Arthritis Centre Versus Arthritis (otherwise known as RACE) has helped move basic understanding forward on several processes underpinning inflammatory arthritis, particularly around the immune response.

Take the example of the biology of several key cytokines – a key focus for RACE whose teams have been investigating the master molecular regulators that bring the cytokine network into action, such as microRNAs.

And while much of the work of the Centre – which is actually a collaboration of four universities led by Glasgow – is focused on growing the molecular understanding of initial disease development and refractory disease, they have also so far generated £11m in direct funding for experimental medicine studies which include patient-focused trials.

This includes BioFLARE, a unique clinical trial funded by the Medical Research Council examining the earliest changes that occur in the joint and in the systemic immune system at the precise time of a rheumatoid arthritis flare up.Professor Iain McInnes

“We have a lot of molecular understanding we didn’t have before,” says Professor Iain McInnes, the Centre’s lead who combines a keen interest of the biology of inflammatory arthritis with his clinical role. “We understand much more about the immune disruption in the early phases of disease. Also, we have done a lot of work looking at how the stromal compartment, in particularly fibroblasts in the joints, have a really quite vital and discrete role.”

What he and his colleagues aim to generate is increased knowledge at the molecular level that turns into a “pipeline” of new treatments and diagnostics that will leave clinicians “spoilt for choice”.

The funding from Versus Arthritis – £2.5m for the first five years and now another £2m for phase 2 – comes with the expectation that while much of the work would fall under the basic science category, it all needs to be relevant and translatable to the clinic. In fact, an expert patient panel has been helping to guide research focus on neglected areas.

“While they wanted to support work on early diagnosis, our patient group also wanted to know what was happening for those already afflicted with the disease so we now also are trying to better understand those patients for whom current treatments are not effective,” he says. “There is still a significant group of people for whom we are not able to offer the right therapy. We are looking at a molecular level at how the joint organises itself in such a way that inflammation cannot resolve. This is an enormous unmet need – we are trying to be responsive to the patient view.”

This is one of the key aims for the next five years – working out why some patients do not go into remission. “I want to know more about this group for whom nothing is working. We can’t get every patient into remission and we need to understand why that is for those with newly presenting and established disease,” he says.

The ultimate goal of RACE is to translate that picture of the disease process at the cellular and molecular level into a personalised approach where identification of certain markers can direct treatment and effect a better outcome. Professor McInnes likens it to the targeted approach now in use in the treatment of some cancers. And he points out that over the past decade the most exciting new treatments have come on the back of molecular discovery.

“There will be new types of therapeutics that become possible, but we will hopefully be able to apply more of a precision model on what therapeutics to use in which patients at what time. I would hope in future that when a person comes into the clinic with inflammatory arthritis, we are able to define their disease at the molecular level allowing us to make the best decisions,” he says, noting that it is a vision that is dependent on continuing funding for pathogenesis research which is a very challenging area at this time.

“I believe we will be making molecularly-based decisions for patients in the next decade that will change patient outcomes. I think we are on the cusp.”

Much of the initial achievement of the Centre, which was initially a collaboration between Glasgow, Birmingham and Newcastle before being joined this year by Oxford, is in the way it has managed to overcome not insubstantial logistical problems which inevitably come with working under a collective banner, says Professor McInnes.

Now that is all in place, and there is a steady stream of PhD students making their way through the Centre, one of the newer focuses for the second “term of office” for RACE is psoriatic arthritis – another key area of unmet need that Professor McInnes is particularly keen to address. One example is work underway directly comparing the molecular expression profiles in cells obtained from rheumatoid arthritis patients with psoriatic arthritis, where both similarities and differences will be informative from a clinical perspective.

“It is a disease begging to give up its secrets but too slowly for my liking – we are going to bring the same focus and approach that we have to rheumatoid arthritis.”

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