Research Breakthrough May Predict Rheumatoid Arthritis
Professor Ursula Fearon in her lab at TBSI. Photo by Trevor Butterworth
By Trevor Butterworth
Steroids, chemotherapy drugs, gold salts. Thirty years ago, these were the only treatments available for people suffering from rheumatoid arthritis. But for a condition affecting about one percent of the population and with a prevalence in women two to three times higher than in men, these medications were marginally effective and mostly toxic. One in ten were lucky: they either tolerated or responded to treatment; for the rest, there was no controlling the disease; the immune system steadily intensified its attack on the joints until cartilage and bone were eaten away.
“You would sometimes see horrendous deformities in their hands and feet,” says Ursula Fearon, Professor of Molecular Rheumatology at Trinity Biomedical Sciences Institute (TBSI). “Within five years of a diagnosis, a patient could be functionally disabled, and over half would be unable to work. The damage was irreversible.”
While rheumatoid arthritis had long been recognized as an autoimmune disease, a result of the body’s innate immune system deciding to attack rather than defend the body, it wasn’t until ground-breaking research identified Tumor Necrosis Factor (TNF), an inflammatory protein present in the inflamed joints, as a trigger for the cytokine cascade that drove the immune response. This meant scientists now had a specific molecule that they could target and block, and clinical trials for medications that blocked TNF produced remarkable results in patients.
“These TNF inhibitors reduced swelling and pain in their joints as well as reducing the fatigue—and more importantly, they stopped progression of the damage in many patients”, says Douglas Veale, Professor and Consultant Rheumatologist at St. Vincent’s University Hospital. “Patients were able to move more freely and resume the activities of daily living. Over the next 10 to 15 years, the patients got their lives back”.
“It was a really exciting time”, says Fearon. “I entered the field in the late 1990s when all these developments were occurring, and by 2000, the prognosis for someone with rheumatoid arthritis had dramatically changed. TNF inhibitors revolutionized the treatment of rheumatoid arthritis for many patients. We started to focus on targeting specific cytokines and cell types in the immune system to modulate the function of these immune cells. We were also able to study the signaling pathways that controlled the interactions between inflammatory pathways and the immune cells”.
While drugs targeting TNF were a turning point for the treatment of rheumatoid arthritis, it wasn’t quite game over, as they do not work for everyone. “A third of patients respond really well to treatment”, says Fearon, “a third have a sub-optimal response and adverse effects; and a third have no response and adverse effects. If we diagnose the patient early, we can change these ratios—the earlier we start the treatment the better the overall response is. But we still need additional or alternative therapies for the sub-optimal and non-responsive groups”.
Currently, it is impossible to predict who will develop the disease or respond to treatment. The treatments are expensive, so a ‘trial and error’ approach is not cost-effective. Then there is the time from disease onset to diagnosis: Even when people go to their doctors complaining of aches and pains, they may show no signs of inflammation or swelling, and, therefore, no clinical evidence of arthritis. “What we need are markers in the blood that correlate with what is going on in the joint”, says Veale. “This will enable us to predict which patients are more likely to get severe disease and target them more aggressively at an earlier stage”.
Finding such markers is one of the goals of a collaboration developed by Fearon between her lab at TBSI, Veale’s research group at St. Vincent’s Hospital, and Arthritis Ireland—bench scientists at the forefront of research, clinicians on the front lines of treatment, and patients and patient advocates without whom this research would be impossible.
On January 19, in a paper published in the journal, Clinical and Translational Immunology (CTI), the scientists and clinicians announced that they had identified abnormal responses in an immune cell, the monocyte CD 14+, before rheumatoid arthritis is clinically detectable.
Primed for insult
“There’s a two-hit hypothesis to why people develop rheumatoid arthritis”, says Dr Megan Hanlon, a Postdoctoral Fellow in Fearon’s lab and one of the lead authors of the CTI study. “It starts with an underlying genetic susceptibility followed by what we call an environmental ‘insult’—an exposure or trigger, such as smoking or an infection. This insult produces a change in a protein in the body’s cells that our immune system then may mistakenly interpret as the arrival of a foreign pathogen”. This first insult primes the immune system to respond aggressively to further insults, and it means a person may now be at risk of developing rheumatoid arthritis. “But”, says, Hanlon, “if we identify how and when this priming occurs—when a person becomes at risk—we may have a window of opportunity to prevent development of the disease”.
As with any detective story, the starting point begins with the scene of the crime, in this case when the joint becomes inflamed. Among the many immune cells responding to this inflammation are macrophages. These are large cells that detect and digest pathogens—and research has found that they consistently reduce in numbers if a patient responds to medication and stay the same if they don’t respond. Currently, they are the only immune cells known to do so.
In simple terms, monocytes mature into macrophages during an inflammatory response. Monocytes are precursor or ‘parent’ white blood cells produced in the bone marrow that circulate in the blood for two or three days before they migrate to the inflamed joint, where they differentiate into macrophages and other cell types depending on the inflammatory environment in the joint.
“We wanted to know whether the monocytes in people with rheumatoid arthritis had a particular gene signature”, says Fearon, “and if so, whether this signature was also present in the circulating monocytes of people at risk of rheumatoid arthritis.”
But they also wanted to understand how cell metabolism affected this process. An emerging body of research over the past ten years has illuminated the way immune cells use energy during an inflammatory response. If they could understand how these metabolic processes alter the inflammatory behaviour of monocytes, it might be possible to devise a way to reprogram the process and thereby reduce or turn off the inflammatory response.
What they found
First, they found that the monocytes circulating in the patient group with rheumatoid arthritis and in the group deemed ‘at risk’ of developing the disease were both behaving differently to those in the control group of healthy subjects: The cells’ characteristics were in a ‘proinflammatory state’— meaning they were poised to trigger inflammation. Notably, there were signals suggesting the monocytes were about to differentiate into macrophages. “Six of the most responsive genes we identified in monocytes from Rheumatoid Arthritis patients were genes that define the signature of an inflammatory macrophage”, says Hanlon. “This is when we got excited”.
Dr Megan Hanlon. Photo by Trevor Butterworth
In a parallel study they also demonstrated that when a monocyte differentiates into a macrophage, the macrophage ‘remembers’ the specific inflammatory function of its monocyte parent. This opened the possibility that analysis of circulatory monocytes—in theory at least—could aid early diagnosis, the ability to monitor the progress of the disease, and, of course, predict response to current therapies. “Now we had evidence suggesting the monocyte cells circulating in the rheumatoid arthritis and ‘at risk’ groups were already primed towards becoming proinflammatory macrophages”, says Fearon. “For the ‘at risk’ group, this also suggested that they were primed to develop rheumatoid arthritis if they experienced a second, probable environmental, insult”.
The TBSI researchers found more evidence of priming when they looked at how the circulating monocytes were metabolizing glucose for energy. “We showed that the monocytes switched pathways from oxidative phosphorylation to glycolysis”, says Fearon. “This allowed them to produce energy at a faster rate to sustain their proinflammatory functions. Then, when we blocked the glycolysis pathway, we were able to dampen the proinflammatory response. “This”, says Professor Fearon, “identifies potential targets for new therapeutic intervention and, importantly, for patients who don’t respond to current treatments”.
This research by Fearon’s lab identifies the unique potential of monitoring circulating monocytes as predictive markers for disease progression and response—and as a marker for the onset of disease. “This will lead to a better understanding of disease progression, help deliver a new approach to predict who is ‘at-risk’ of developing rheumatoid arthritis, and identify new candidate medications for the treatment of arthritis sufferers”, says Fearon. “Our goal with these studies is to improve the quality of life for those currently living with rheumatoid arthritis and, ultimately, find a cure.”
From bench to bedside and back again
None of the novel research by Fearon’s lab at TBSI would have been possible without collaboration with Veale’s research group at the Centre for Arthritis and Rheumatic Diseases at St. Vincent’s University Hospital—and the outreach campaigns run by Arthritis Ireland to reach GPs and recruit patients.
“People with very few symptoms are difficult to find”, says Veale, “as they tend not to complain to their doctors until the symptoms become active and painful”. The clinicians relied on GPs checking for the presence of two autoantibodies, Rheumatoid Factor and anti‐Citrullinated Protein Antibody (ACPA), which indicated potential risk in patients who had complained of diffuse aches and pains but did not show any clinical signs of inflammation.
“This is where Arthritis Ireland has been extremely supportive”, says Veale. “They’ve got a very good outreach network and they’ve even raised money to help build a national network for research”.
“Without the patients, and their willingness to give us tissue and blood”, says Fearon, “we simply wouldn’t be able to do this meaningful translational research”.
“Right now”, says Fearon, “we’re looking to see what happens long term. The inflammatory and metabolic monocyte signature provides a way of tracking what is happening in ‘at-risk’ individuals and patients with rheumatoid arthritis. Will it predict which ‘at-risk’ individuals will convert to rheumatoid arthritis and will it predict the disease’s progression and response? These are key questions to be answered in our goal to achieve remission and, ultimately, find a cure; however, it takes a lot of patience.”
“We’re also looking at the complex interplay between inflammatory signaling and metabolism and how they both influence each other”, she says. “We’ve made some really interesting discoveries about the macrophage in the synovial tissue that we have just submitted as a paper”.
Veale wants to expand the current cohort of patients by recruiting first-degree relatives of existing patients, given that there is a significant number who have a known family history of rheumatoid arthritis and who may have a genetic predisposition to the condition. And, of course, there is the tantalizing prospect of identifying another molecule or hierarchy of molecules as a therapeutic target. “The more specific a new treatment”, says Veale, “the safer it is likely to be.”
The research—and particularly the metabolic findings—have triggered lots of interest from potential collaborators. For Veale, it is an example of what can happen when medical doctors and research scientists respect and take the time to understand each other’s knowledge and experience. “That’s the great thing about our team, everybody—the clinical doctors, the clinical nurses, and the scientists—engages on a very, very meaningful level”, he says. “We each understand what the other is talking about because we spend the time trying to understand and speak the same language”.
Trevor Butterworth is an adjunct assistant professor of science communication in TBSI. He founded Sense About Science USA, is co-founder and VP of Indicio.tech, and acting executive director of the Cardea steering group at Linux Foundation Public Health.