Unlocking the key to early prevention of rheumatoid arthritis would be a real game-changer and researchers have found what could be central to this: enhancing the gut microbiome. Dr Chris Rooney and Professor Kulveer Mankia, experts in medical microbiology and rheumatology respectively, speak to Julie Penfold about their latest research and how their findings could positively impact clinical practice and optimise patient care.
The gut microbiome is the largest and most complex microbiome in the human body and understanding of its importance in health is increasing exponentially, with research into its impact on multiple conditions ramping up.
Dr Chris Rooney, medical microbiologist at Leeds Teaching Hospitals NHS Trust and clinical lecturer in microbiology at the University of Leeds, has a longstanding interest in the dynamics of the gut microbiome in inflammatory diseases, particularly rheumatoid arthritis.
A perfect storm of contributing factors led to an ideal opportunity to carry out a longitudinal study into the dynamics of the gut microbiome in patients at risk of developing rheumatoid arthritis and work for the pilot study began in 2017/18.
‘The fact that [the gut microbiome is] constantly lying on the mucosal surface, so there’s always that interaction with the immune system, was a real area of interest,’ Dr Rooney explains. ‘When we began the initial work for this study, sequencing technologies were becoming more widely available and less costly so there was a culmination of my own interest and advancing science at the time.
‘Additionally, Leeds has a strong background in musculoskeletal research and a very unique cohort of individuals that are at risk of rheumatoid arthritis. We rarely can study a disease before its onset, so it was a very unique opportunity to see how the gut microbiome can influence or be influenced by the development of this disease.’
The current picture of rheumatoid arthritis
Professor Kulveer Mankia, professor of clinical and translational rheumatology at the University of Leeds and a consultant rheumatologist at Leeds Teaching Hospitals NHS Trust, brought his internationally renowned expertise in rheumatoid arthritis risk factors and early diagnosis to Dr Rooney’s research.
‘We’re getting much better at being able to predict rheumatoid arthritis development in at-risk patients,’ he explains. ‘The main risk factor is having [cyclic citrullinated peptide] CCP antibodies along with joint pain and joint stiffness. We’re now able to use this to inform therapeutic studies with the aim of preventing or intercepting rheumatoid arthritis onset.’
Interception therapy can include giving patients a six-month or one-year drug treatment, then stopping this and assessing whether it’s had an impact on halting the disease progression.
‘There’s been a handful of trials published looking at pharmacotherapies, including the biologic medication abatacept, and also methotrexate and hydroxychloroquine,’ Professor Mankia explains. ‘We’ve seen encouraging results particularly with abatacept showing that you can certainly delay disease progression significantly. It appears to be able to prevent arthritis onset in a subgroup of patients too.’
The role of the gut microbiome in rheumatoid arthritis
Patients at risk of rheumatoid arthritis who are experiencing initial symptoms may feel a sense of hopelessness that developing arthritis is inevitable. But Dr Rooney and Professor Mankia’s longitudinal study identified that there are signs in the gut microbiome that can indicate rheumatoid arthritis in evolution several months before a patient will go onto develop the condition, which may mean steps can be taken to halt progression.
‘There have been a number of studies that have shown if you have established rheumatoid arthritis, your gut microbiome is different,’ Dr Rooney explains. ‘But we wanted to learn whether individuals who were at risk of rheumatoid arthritis had a different gut microbiome. In Leeds, we had the unique ability to study this via longitudinal sampling to allow us to see changes over time.’
This change is something that hasn’t previously been studied due to the dynamic nature of the gut microbiome, he says, adding that ‘if you measure your microbiome today and in a month’s time, it will be roughly the same, but it won’t be exactly the same.’
As part of their research study, 19 patients who were at risk of developing rheumatoid arthritis provided five samples over a 15-month period. This enabled Dr Rooney to track changes in their gut microbiome and assess how this translated to disease onset.
‘What we found is that individuals who are at risk of rheumatoid arthritis have an increase in specific strains of prevotella bacteria, which is associated with their underlying risk profile,’ he explains.
Five patients progressed to having clinical rheumatoid arthritis over the study period. The sampling showed they had gut instability, with higher amounts of bacteria, including prevotella, approximately 10 months before the arthritis developed.
Interestingly, the remaining participants who did not progress to rheumatoid arthritis had largely stable amounts of bacteria in their gut.
Moving towards a personalised treatment approach
The aim is to take these observations forward and develop personalised interventions to prevent rheumatoid arthritis onset and progression, explains Professor Mankia.
‘If we can understand microbiome changes that underpin the development of rheumatoid arthritis and compare those to people who appear safe from progression, this would hopefully lead to an interventional approach,’ he says.
‘Once we pin those changes down, we could introduce an intervention such as a probiotic treatment that could shift the microbiome in a favourable direction. I think that’s where this research would be heading towards.’
There are also parallels with other mucosal sites, Professor Mankia adds, particularly with the oral cavity and how this may relate to rheumatoid arthritis onset and the potential for personalised treatment approaches for those at risk.
This could include potentially sampling multiple mucosal sites to see where there are abnormalities and what the target might be for an intervention. For example, opting for a combined gut-oral approach, or focusing more on one site depending on a patient’s individual profile and preference.
‘It could also be an approach that works in parallel with drug treatments,’ says Professor Mankia. ‘The aim is to be able to personalise treatment to offer different types of interventions that are tailored to a patient’s particular situation and risk factors.’
For Dr Rooney, this aligns with his current research into functional changes in the gut microbiome of individuals at-risk of rheumatoid arthritis, looking at the molecules and substances that are either lacking or overabundant.
‘We want to see whether if we change the gut microbiome itself, not just supplementing the molecules, whether this would make a difference,’ he explains. This could be through introducing new strains of bacteria or making changes to an individual’s diet, for example, and it’s where we would like to go with our research.’
The gut microbiome impact on clinical care
In rheumatology, there is a strong interest in non-pharmaceutical approaches to autoimmune condition management. This is being driven by patients asking for a different approach to taking a pill or having an injection, Professor Mankia says, which may relate to concerns about the risk of side effects with rheumatoid arthritis drug treatments.
Clinicians are also becoming increasingly aware of dietary factors and the role they potentially play in autoimmune disease. For example, omega 3 and vitamin D levels and following a low salt diet.
‘These areas, including the links between rheumatoid and periodontal disease, are all growing in terms of the data, and this research very much adds to the evidence that’s emerging,’ explains Professor Mankia. ‘For practising clinicians, I think it’s just having an awareness of those other factors that could be driving autoimmune disease. Being aware that, as we go forward, there will be more data around non-pharmaceutical approaches so they can advise patients about these right from the beginning of their disease.’
Professor Mankia is currently recruiting patients for a drug trial that will test the efficacy of a Janus kinase inhibitor in people at high risk of rheumatoid arthritis. The aim of the trial is to see if the drug prevents disease onset. He is also involved in research looking at the changes that occur in the immune system when patients go from being at risk to developing rheumatoid arthritis.
‘It’s then bringing all this together into understanding how the mucosal surfaces and the microbiome interact with the circulating immune system, and, ultimately, how this affects the joints and tissues that become inflamed and damaged with rheumatoid arthritis,’ Professor Mankia adds.
