Professor Ranjeny Thomas talks about the multi-centre trial to test RA remission without csDMARDs.
Rheumatologists may be getting closer to having a game-changing tool in their arsenal, with early stage clinical trials on a world-first “immune-reset” therapy for rheumatoid arthritis planned for next year.
A year on from the announcement of a $11.54 million federal grant through the Medical Research Future Fund, the researchers are preparing to start early stage clinical trials in a year.
The treatment is known as an antigen-specific tolerising immunotherapy, which instructs the immune system to tolerate joint proteins, with the goal for patients to retain remission after stopping treatment with conventional anti-rheumatic medicines.
If successful in clinical trials the immunotherapy has the potential to revolutionise the treatment of RA.
Professor Thomas, a rheumatologist and researcher at the University of Queensland, Translational Research Institute, told Rheumatology Republic the Reset Rheumatoid Arthritis project was progressing a second-generation product for testing in future clinical trials. Their work that began in 2000 has progressed through two proof-of-concept trials.
“It certainly makes such a difference to have really good investment from the government,” she said. “It’s a big collaborative project which is well-funded and is bringing together researchers across Australia and in Europe, the US and the UK to progress the development and clinical trials of the novel immune therapy.”
Arthritis Australia and the Australian Rheumatology Associations are key partners in the Reset RA project, along with teams at Monash University, Macquarie University, Flinders University, University of Sydney, Queensland Health, Kings College London, Newcastle University and Leiden University Medical Center.
The innovative approach involves a liposome-encapsulated therapy that combines a self-peptide derived from the synovial tissue of rheumatoid patients with calcitriol (vitamin D).
When injected into the skin, the treatment aims to modulate dendritic cells, suppressing inflammatory responses and inducing immune tolerance.
“So it works with a vaccine-like action, but the dendric cells that pick it up in the skin are suppressed when they present this antigen in lymph nodes, which regulates antigen-specific lymphocytes,” Professor Thomas told RR.
“It is fairly simple in concept. It’s taken a long time to get it to this stage [as] it’s a really long journey to get here, but it’s exciting because we’re now at the pointy end where we get to put it into patients and test out whether it’s going to induce tolerance towards a rheumatoid antigen, to create prolonged remission in patients with recent onset who are already in remission on csDMARDS [conventional synthetic disease modifying antirheumatic drugs].
“And if we can do that, create a really good, deep remission safely in those patients, what we want to do is to be able to take them off their csDMARDS.”
Professor Thomas said the exciting potential of this treatment was to reduce the need for patients to take drugs for life. “We aim to provide a long remission, and to prevent the usual flares when they stop current drugs,” she explained.
“The other benefits would be reducing the risk of side effects from current drugs and promoting long remission times, which we know will have better outcomes for patients.”
How long in theory that remission will last in the average patient is a question the researchers hope to answer in the trials.
“We’d want that to last forever of course, but we’ll start by testing safety with different doses, how much and how often to dose and the associated safety,” said Professor Thomas.
“With that information we will test people who are in remission to see if we can safely prolong the time to flare after stopping DMARDs in people getting a course of immunotherapy compared to those who do not.”
The target population is patients with recent-onset RA in drug-induced remission, while the primary goal is to achieve prolonged remission and potentially eliminate the need for long-term medication.
Professor Thomas said the current stage of the project involved preparing and developing biomarkers for clinical trials planned to commence during the second half of next year. She said they were planning to recruit about 100 patients across multiple stages.
She said there were two big areas of unmet need in RA – drug-free remission and drug-refractory disease. She said the latter cohort is generally at a later disease stage and probably needed a different kind of drug development than the immunotherapy being investigated in Reset RA.
And of course that brings the conversation back to the importance of early diagnosis in achieving better outcomes in the short and long term.
“Helen Benham and I published a study on this from Brisbane in 2015, and when we looked at the delays to presentation at the early arthritis clinic, the total delay from symptom onset to rheumatology review was 26 weeks. The biggest delay was patient-related, that is in presenting to the GP. There was also some delay in the GP referring, related to more insidious onset disease,” she said.
“Patient delay reflects the experience of other early arthritis clinics worldwide. I think this reflects the patient experience too. When we’ve talked to consumers, unless the onset is explosive, at the start of their disease, they often put up with symptoms, which are often episodic. Or, especially when seronegative, some go to the GP multiple times before they are referred to a specialist.
“In practice, outside an early arthritis clinic, there can be more delay in getting new onset RA patients seen if there is no triage. So I think that’s a model of care situation we need to try to fix generally, so that based on criteria cases of likely rheumatoid arthritis can be seen early.
“That’s worked really well in settings where there’s a very highly organised health system, like in the Netherlands and the UK, where there’s early arthritis clinics dotted around the country, and the patients can be seen early and seen frequently to treat to target in an early arthritis setting.
“Outside that setting, it tends to be a much more ad hoc, and worse as you get further from the cities. If there were a way to really improve outcomes and even cure patients early, we need to think about our model of care in Australia to make it more feasible for all people to be diagnosed and managed early.
“We still need to educate the GPs to send the patients, you know, so that they understand what early symptoms are like and the red flags for early referral.”
Complementing the immunotherapy trials, researchers are simultaneously conducting the “RA-HEAL” trial, investigating lifestyle interventions that may improve both quality of life and immune function.
University of Queensland researchers are looking for volunteers to participate in the trial, including people who have been diagnosed with RA in the past year; are motivated to make positive lifestyle changes; and able to attend sessions in South-East Queensland.
“Positive wellbeing and healthy habits are important for people with RA. We want to know how we can help people with RA start and continue healthy and resilience activities. This research is comparing two different ways to help people with arthritis,” Professor Thomas said.
“We will be looking at changes in quality of life, physical function, diet, RA disease control, and immune function, which we are expecting based on our previous pilot study.”
For more information about the RA-HEAL see here.
