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18-11-2022 | ACR 2022 | Conference coverage | News

A Great Debate: To treat or not to treat in pre-RA?

Author: Lucy Piper

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medwireNews: In one of two Great Debate sessions at ACR Convergence 2022 in Philadelphia, Pennsylvania, USA, two experts teamed up to provide opposing stands on whether now is the right time to be treating people at risk for rheumatoid arthritis (RA) in the preclinical stages of the condition in order to prevent disease onset.

“We would argue that not treating subclinical RA is the right thing to do in 2022,” said Hani El-Gabalawy (University of Manitoba, Winnipeg, Canada), stating the case not to treat alongside Janet Pope (University of Western Ontario, London, Canada). “At this point in time, if you look at people who are ACPA [anti-citrullinated protein antibody]-positive, for example, it’s impossible to know who are going to progress to clinical RA and who is not.”

In favor of treating people with subclinical RA, speaking together with V Michael Holers (University of Colorado, Boulder, Denver, USA), Kevin Deane (University of Colorado) believes “we should try and prevent or ameliorate clinical RA by treating in a stage-specific manner pre-RA autoimmune processes that may have their own symptoms and tissue injury,” adding that treating at a stage even when inflammatory arthritis is not present could still provide benefits such as reduced pain or fatigue.

What defines pre-RA?

Deane opened the debate and outlined his rationale in favor of treating pre-RA, which included the limited efficacy of treatments for clinical RA; the financial cost of RA at the individual and population level; its adverse effect on wellbeing and mortality; and the fact that even if not preventing RA, early treatment could lead to a more benign form of RA, as shown in TREAT EARLIER.

He defined this pre-RA stage as when “someone has definable autoimmunity but doesn’t yet have clinically apparent rheumatoid arthritis or clinical RA.”

The focus needs to be on the non-articular stage, “otherwise aren’t you really just treating clinical RA – even if ‘subclinical’?” he proposed.

In her case opposing the treatment of pre-RA, Pope highlighted the lack of agreement among clinicians on what pre-RA actually is. Definitions include being ACPA- or rheumatoid factor (RF)-positive, ACPA-positive with arthralgia, or arthralgia with abnormal ultrasound in one or more joints. She said that this in turn makes “it difficult to sell that you are going to treat someone when they don’t have an actual defined disease yet.”

What are we treating in pre-RA?

Deane and Holers believe understanding the biology of RA development and its variability or endotypes across different stages, notably the non-articular stage, is key to defining accurate criteria for risk stratification.

Holers referred to the causal endotypes hypothesis, which he said researchers are “increasingly coming to understand.”

The hypothesis is based on abnormalities associated with mucosal mechanisms that promote initial loss of self-tolerance to citrullinated antigens and are unseen but cause people to be “immunologically unwell.” These abnormalities may include Epstein Barr virus infection, periodontal disease, and autoantibody production in the lung and gut.

“The lung and the gut are the two areas [in which] we are increasingly convinced that there is ongoing local autoantibody production and ongoing local processes that will ultimately lead to systemic disease and targeting of the joints,” Holers explained.

He believes that “a strong candidate in a subset of individuals for this kind of causal endotype” is a true atherogenic bacteria – Subdoligranulum didolesgii – which was found in the feces of a subset of individuals at risk for RA, but not in controls, as presented in a poster at the conference by Meagan Chriswell  (University of Colorado).

These different endotypes may then play a role in, for instance, the type of RA, the timing and evolution of development, autoantibody status, phenotypes, and clinical responses, and allow for a mechanism-based approach to treating and correcting causal processes to prevent RA, Holers explained.

However, El-Gabalawy pointed out the problems of treating during these early stages, including that some B cells recognize more than one post-translational modification “and we really don’t know how that works.” Moreover, there are difficulties for clinicians in terms of carrying out multi-antigen arrays to determine antibody spreading and evolution of pathogenic autoimmunity.

He did see an opportunity for ACPA V-domain glycosylation, however, as a key biomarker of ACPA maturation. “If we could develop some kind of a high throughput assay for this, this might be a very good way of understanding who is more at risk than others.”

But he said that if we then treat with DMARDs at this point “it’s too late for prevention; the immune system is fully primed and the synovium is targeted and engaged and all we can do is delay […] and that is what the clinical trials I believe are showing us right now.”

Who should we treat?

Pope pointed out that the numbers of early RA patients who are ACPA-positive is about 64% at most, so in terms of prevention efforts we “are missing at least a third of patients anyway.”

And the numbers in the general population are even lower, Pope stressed, citing a study by A van Zanten et al showing that in a general population cohort of more than 40,000 people, 1.4% of those older than 50 years were ACPA-positive and of these only half had RA.

Even among those individuals who are ACPA- and RF-positive, there is about a “50–50 split” in the percentage of individuals who go on to develop RA after 5 years and those who go on to become seronegative, at 40% in both cases, said El-Gabalawy, based on findings from one of his 2019 studies. Therefore, “it is very difficult for us at this point to know who is going to do what.”

Given these small numbers, Pope proposed that treating pre-RA may actually do more harm than good

“Let’s assume you see a person with a strongly positive ACPA but no arthralgias,” said Pope. “At most one in five patients, so out of six patients, one will develop RA over the next year or up to 3 years, but that means that five won’t. So the number needed to treat to prevent one RA over the next year is five or six.

“But the number needed to treat doing nothing is actually the very same with most molecules that we have looked at,” and so “we could overtreat four or five people who never develop RA, assuming we have a drug that prevents RA, or do nothing which would not be very different,” she explained.

Deane commented, however, that treatment of pre-RA “may not involve ‘established’ DMARDS,” but also include lifestyle changes and recognized the need to “shift our mindset from DMARDs, which we now think of in terms of drugs, to disease-modifying approaches.”

Recognizing the potential impact of treating or not treating pre-RA

In her closing comments, Pope invited the audience to consider the impact of treating and following up five times more patients with no inflammatory arthritis and the increased burden this would have on rheumatologic care as well as a potential increase in the use of imaging facilities and medications that may not even stop or prevent RA.

She said: “I think we have money better spent on promoting healthy lifestyles, decreasing the diseases that affect the population, and frankly some of the interventions on lifestyles would be the same things that could decrease carcinoma and cardiovascular diseases.”

Indeed, she reported recent findings from Jill Hahn and team showing that a healthy lifestyle can reduce the risk for RA in women by up to a third and the VITAL trial in which vitamin D, with or without omega-3 fatty acid supplementation, was found to reduce incident RA in at-risk individuals.

El-Gabalawy also made a final point that “if we did treat this [pre-RA] population with existing therapies that only delay the onset [of RA], how are we going to find study participants to discover treatments that really prevent RA?”

Deane agreed that “we don’t want to just treat a biomarker without a disease”, and there is a need to “understand the biomarkers better.” However, he believes “the time is now to move ahead very quickly with understanding all of this.” And Holers added that “autoimmune diseases are going to be vastly changed by understanding the actual causal drivers of the disease” and suggests that in terms of intervention “we are going to be using a different type of drug, a different style of drug” to the DMARDs currently used.

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ACR Convergence 2022; Philadelphia, Pennsylvania, USA: November 10–14